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Showing 1 - 200 of 3562 Journals sorted alphabetically
16 de Abril     Open Access  
3D Printing in Medicine     Open Access  
AADE in Practice     Hybrid Journal   (Followers: 5)
ABCS Health Sciences     Open Access   (Followers: 3)
Abia State University Medical Students' Association Journal     Full-text available via subscription  
ACIMED     Open Access   (Followers: 1)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 41)
Acta Bio Medica     Full-text available via subscription   (Followers: 2)
Acta Bioethica     Open Access  
Acta Bioquimica Clinica Latinoamericana     Open Access   (Followers: 1)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Informatica Medica     Open Access   (Followers: 1)
Acta Medica (Hradec Králové)     Open Access  
Acta Medica Bulgarica     Open Access  
Acta Medica Colombiana     Open Access   (Followers: 1)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Medica Indonesiana     Open Access  
Acta Medica International     Open Access  
Acta medica Lituanica     Open Access  
Acta Medica Marisiensis     Open Access  
Acta Medica Martiniana     Open Access  
Acta Medica Nagasakiensia     Open Access  
Acta Medica Peruana     Open Access   (Followers: 2)
Acta Médica Portuguesa     Open Access  
Acta Medica Saliniana     Open Access  
Acta Scientiarum. Health Sciences     Open Access   (Followers: 1)
Acupuncture & Electro-Therapeutics Research     Full-text available via subscription   (Followers: 4)
Acupuncture and Natural Medicine     Open Access  
Addiction Science & Clinical Practice     Open Access   (Followers: 6)
Addictive Behaviors Reports     Open Access   (Followers: 8)
Adıyaman Üniversitesi Sağlık Bilimleri Dergisi / Health Sciences Journal of Adıyaman University     Open Access  
Adnan Menderes Üniversitesi Sağlık Bilimleri Fakültesi Dergisi     Open Access  
Advanced Biomedical Research     Open Access  
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Science, Engineering and Medicine     Partially Free   (Followers: 7)
Advances in Bioscience and Clinical Medicine     Open Access   (Followers: 5)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28)
Advances in Life Course Research     Hybrid Journal   (Followers: 8)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Medical Education and Practice     Open Access   (Followers: 25)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Medicine     Open Access   (Followers: 2)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4)
Advances in Molecular Oncology     Open Access   (Followers: 2)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7)
Advances in Parkinson's Disease     Open Access  
Advances in Phytomedicine     Full-text available via subscription  
Advances in Preventive Medicine     Open Access   (Followers: 5)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
Advances in Skeletal Muscle Function Assessment     Open Access  
Advances in Therapy     Hybrid Journal   (Followers: 5)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
Advances in Wound Care     Hybrid Journal   (Followers: 10)
African Health Sciences     Open Access   (Followers: 2)
African Journal of Biomedical Research     Open Access  
African Journal of Clinical and Experimental Microbiology     Open Access   (Followers: 1)
African Journal of Laboratory Medicine     Open Access   (Followers: 2)
African Journal of Medical and Health Sciences     Open Access   (Followers: 2)
African Journal of Trauma     Open Access   (Followers: 1)
Afrimedic Journal     Open Access   (Followers: 2)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
AIDS Research and Human Retroviruses     Hybrid Journal   (Followers: 8)
AJOB Primary Research     Partially Free   (Followers: 3)
AJSP: Reviews & Reports     Hybrid Journal  
Aktuelle Ernährungsmedizin     Hybrid Journal   (Followers: 4)
Al-Azhar Assiut Medical Journal     Open Access  
Alexandria Journal of Medicine     Open Access   (Followers: 1)
Allgemeine Homöopathische Zeitung     Hybrid Journal   (Followers: 2)
Alpha Omegan     Full-text available via subscription  
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3)
American Journal of Biomedical Engineering     Open Access   (Followers: 12)
American Journal of Biomedical Research     Open Access   (Followers: 2)
American Journal of Biomedicine     Full-text available via subscription   (Followers: 7)
American Journal of Chinese Medicine, The     Hybrid Journal   (Followers: 4)
American Journal of Clinical Medicine Research     Open Access   (Followers: 6)
American Journal of Family Therapy     Hybrid Journal   (Followers: 11)
American Journal of Law & Medicine     Full-text available via subscription   (Followers: 11)
American Journal of Lifestyle Medicine     Hybrid Journal   (Followers: 5)
American Journal of Managed Care     Full-text available via subscription   (Followers: 11)
American Journal of Medical Case Reports     Open Access   (Followers: 1)
American Journal of Medical Sciences and Medicine     Open Access   (Followers: 3)
American Journal of Medicine     Hybrid Journal   (Followers: 43)
American Journal of Medicine and Medical Sciences     Open Access   (Followers: 1)
American Journal of Medicine Studies     Open Access  
American Journal of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American Journal of the Medical Sciences     Hybrid Journal   (Followers: 12)
American Journal on Addictions     Hybrid Journal   (Followers: 7)
American medical news     Free   (Followers: 3)
American Medical Writers Association Journal     Full-text available via subscription   (Followers: 4)
Amyloid: The Journal of Protein Folding Disorders     Hybrid Journal   (Followers: 5)
Anales de la Facultad de Medicina     Open Access  
Anales de la Facultad de Medicina, Universidad de la República, Uruguay     Open Access  
Anales del Sistema Sanitario de Navarra     Open Access   (Followers: 1)
Analgesia & Resuscitation : Current Research     Hybrid Journal   (Followers: 5)
Anatolian Clinic the Journal of Medical Sciences     Open Access  
Anatomical Science International     Hybrid Journal   (Followers: 2)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1)
Anatomy     Open Access  
Anatomy Research International     Open Access   (Followers: 2)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3)
Ankara Medical Journal     Open Access   (Followers: 2)
Ankara Üniversitesi Tıp Fakültesi Mecmuası     Open Access  
Annales de Pathologie     Full-text available via subscription  
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annals of African Medicine     Open Access   (Followers: 1)
Annals of Anatomy - Anatomischer Anzeiger     Hybrid Journal   (Followers: 2)
Annals of Bioanthropology     Open Access   (Followers: 4)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18)
Annals of Biomedical Sciences     Full-text available via subscription   (Followers: 3)
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 10)
Annals of Family Medicine     Open Access   (Followers: 12)
Annals of Fundeni Hospital     Open Access   (Followers: 1)
Annals of Ibadan Postgraduate Medicine     Open Access  
Annals of Medical and Health Sciences Research     Open Access   (Followers: 7)
Annals of Medicine     Hybrid Journal   (Followers: 12)
Annals of Medicine and Surgery     Open Access   (Followers: 7)
Annals of Microbiology     Hybrid Journal   (Followers: 10)
Annals of Nigerian Medicine     Open Access   (Followers: 1)
Annals of Saudi Medicine     Open Access  
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5)
Annals of The Royal College of Surgeons of England     Full-text available via subscription   (Followers: 3)
Annual Reports in Medicinal Chemistry     Full-text available via subscription   (Followers: 7)
Annual Reports on NMR Spectroscopy     Full-text available via subscription   (Followers: 4)
Annual Review of Medicine     Full-text available via subscription   (Followers: 17)
Anthropological Review     Open Access   (Followers: 23)
Anthropologie et santé     Open Access   (Followers: 5)
Antibiotics     Open Access   (Followers: 9)
Antibodies     Open Access   (Followers: 2)
Antibody Technology Journal     Open Access   (Followers: 1)
Anuradhapura Medical Journal     Open Access  
Anwer Khan Modern Medical College Journal     Open Access   (Followers: 2)
Apmis     Hybrid Journal   (Followers: 1)
Apparence(s)     Open Access   (Followers: 1)
Applied Clinical Research, Clinical Trials and Regulatory Affairs     Hybrid Journal  
Applied Medical Informatics     Open Access   (Followers: 10)
Arab Journal of Nephrology and Transplantation     Open Access   (Followers: 1)
Arak Medical University Journal     Open Access  
Archive of Clinical Medicine     Open Access   (Followers: 1)
Archive of Community Health     Open Access   (Followers: 1)
Archives Medical Review Journal / Arşiv Kaynak Tarama Dergisi     Open Access  
Archives of Medical and Biomedical Research     Open Access   (Followers: 3)
Archives of Medical Laboratory Sciences     Open Access   (Followers: 1)
Archives of Medicine and Health Sciences     Open Access   (Followers: 3)
Archives of Medicine and Surgery     Open Access  
Archives of Trauma Research     Open Access   (Followers: 3)
Archivos de Medicina (Manizales)     Open Access  
ArgoSpine News & Journal     Hybrid Journal  
Arquivos Brasileiros de Oftalmologia     Open Access  
Arquivos de Ciências da Saúde     Open Access  
Arquivos de Medicina     Open Access  
Ars Medica : Revista de Ciencias Médicas     Open Access  
ARS Medica Tomitana     Open Access   (Followers: 1)
Art Therapy: Journal of the American Art Therapy Association     Full-text available via subscription   (Followers: 11)
Arterial Hypertension     Open Access   (Followers: 1)
Artificial Intelligence in Medicine     Hybrid Journal   (Followers: 12)
Artificial Organs     Hybrid Journal   (Followers: 1)
ASHA Leader     Open Access  
Asia Pacific Family Medicine     Open Access   (Followers: 1)
Asia Pacific Journal of Clinical Nutrition     Full-text available via subscription   (Followers: 10)
Asia Pacific Journal of Clinical Trials : Nervous System Diseases     Open Access  
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Health     Open Access   (Followers: 3)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 3)
Asian Journal of Medical and Pharmaceutical Researches     Open Access   (Followers: 1)
Asian Journal of Medical Sciences     Open Access   (Followers: 2)
Asian Journal of Scientific Research     Open Access   (Followers: 3)
Asian Journal of Transfusion Science     Open Access   (Followers: 1)
Asian Medicine     Hybrid Journal   (Followers: 5)
Asian Pacific Journal of Cancer Prevention     Open Access  
ASPIRATOR : Journal of Vector-borne Disease Studies     Open Access  
Astrocyte     Open Access  
Atención Familiar     Open Access  
Atención Primaria     Open Access   (Followers: 1)
Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche     Open Access  
Audiology - Communication Research     Open Access   (Followers: 8)
Auris Nasus Larynx     Full-text available via subscription  
Australian Coeliac     Full-text available via subscription   (Followers: 1)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 1)
Autopsy and Case Reports     Open Access  
Aviation, Space, and Environmental Medicine     Full-text available via subscription   (Followers: 10)
Avicenna     Open Access   (Followers: 3)
Avicenna Journal of Clinical Medicine     Open Access  
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)
Bangladesh Journal of Anatomy     Open Access   (Followers: 1)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Medical Biochemistry     Open Access   (Followers: 3)
Bangladesh Journal of Medical Education     Open Access   (Followers: 2)
Bangladesh Journal of Medical Microbiology     Open Access   (Followers: 3)
Bangladesh Journal of Medical Physics     Open Access  
Bangladesh Journal of Medical Science     Open Access  
Bangladesh Journal of Medicine     Open Access   (Followers: 1)
Bangladesh Journal of Physiology and Pharmacology     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Bangladesh Medical Journal     Open Access  

        1 2 3 4 5 6 7 8 | Last

Journal Cover
Advances in Protein Chemistry and Structural Biology
Journal Prestige (SJR): 0.791
Citation Impact (citeScore): 2
Number of Followers: 19  
  Full-text available via subscription Subscription journal
ISSN (Online) 1876-1623
Published by Elsevier Homepage  [3163 journals]
  • The OECD Principles for (Q)SAR Models in the Context of Knowledge
           Discovery in Databases (KDD)
    • Authors: Gabriela Gomez-Jimenez; Karla Gonzalez-Ponce; Durbis J. Castillo-Pazos; Abraham Madariaga-Mazon; Joaquin Barroso-Flores; Fernando Cortes-Guzman; Karina Martinez-Mayorga
      Abstract: Publication date: Available online 4 May 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Gabriela Gomez-Jimenez, Karla Gonzalez-Ponce, Durbis J. Castillo-Pazos, Abraham Madariaga-Mazon, Joaquin Barroso-Flores, Fernando Cortes-Guzman, Karina Martinez-Mayorga
      The steps followed in the knowledge discovery in databases (KDD) process are well documented and are widely used in different areas where exploration of data is used for decision making. In turn, while different workflows for developing quantitative structure–activity relationship (QSAR) models have been proposed, including combinatorial use of QSAR, there is now agreement on common requirements for building trustable predictive models. In this work, we analyze and confront the steps involved in KDD and QSAR and present how they comply with the OECD principles for the validation, for regulatory purposes, of QSAR models.

      PubDate: 2018-05-28T16:21:27Z
      DOI: 10.1016/bs.apcsb.2018.04.001
  • Linear Analogues of the Lipopeptide Battacin With Potent In Vitro Activity
           Against S. aureus
    • Authors: Hugh D. Glossop; Esperanza Pearl; Gayan H. De Zoysa; Vijayalekshmi Sarojini
      Abstract: Publication date: Available online 6 April 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Hugh D. Glossop, Esperanza Pearl, Gayan H. De Zoysa, Vijayalekshmi Sarojini
      Eight linear analogues of the lipopeptide battacin were evaluated for their antibacterial activity against the Gram-positive Staphylococcus aureus. Of this library, the enantiomeric lipopeptide analogue 9.4 exhibited nanomolar inhibitory activity (MIC=200nmol) against S. aureus. Furthermore, this lipopeptide was resilient toward degradation conditions when exposed to rat serum proteases for up to 8h.

      PubDate: 2018-04-16T01:56:04Z
      DOI: 10.1016/bs.apcsb.2018.03.004
  • Chimeric Small Antibody Fragments as Strategy to Deliver Therapeutic
    • Authors: Sandra Aguiar; Joana Dias; Ana M. Manuel; Roberto Russo; Pedro M.P. Gois; Frederico A. da Silva; Joao Goncalves
      Abstract: Publication date: Available online 6 April 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Sandra Aguiar, Joana Dias, Ana M. Manuel, Roberto Russo, Pedro M.P. Gois, Frederico A. da Silva, Joao Goncalves
      Antibody–drug conjugates (ADCs) represent an innovative class of biopharmaceuticals, which aim at achieving a site-specific delivery of cytotoxic agents to the target cell. The use of ADCs represents a promising strategy to overcome the disadvantages of conventional pharmacotherapy of cancer or neurological diseases, based on cytotoxic or immunomodulatory agents. ADCs consist of monoclonal antibodies attached to biologically active drugs by means of cleavable chemical linkers. Advances in technologies for the coupling of antibodies to cytotoxic drugs promise to deliver greater control of drug pharmacokinetic properties and to significantly improve pharmacodelivery applications, minimizing exposure of healthy tissue. The clinical success of brentuximab vedotin and trastuzumab emtansine has led to an extensive expansion of the clinical ADC pipeline. Although the concept of an ADC seems simple, designing a successful ADC is complex and requires careful selection of the receptor antigen, antibody, linker, and payload. In this review, we explore insights in the antibody and antigen requirements needed for optimal payload delivery and support the development of novel and improved ADCs for the treatment of cancer and neurological diseases.

      PubDate: 2018-04-16T01:56:04Z
      DOI: 10.1016/bs.apcsb.2018.03.002
  • Protein and Peptides for Elderly Health
    • Authors: Nan Shang; Chalamaiah Meram; Nandika Bandara; Jianping Wu
      Abstract: Publication date: Available online 5 April 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Nan Shang, Chalamaiah Meram, Nandika Bandara, Jianping Wu
      The world is aging rapidly; thus, the management of elderly health at an advanced age poses a new research challenge. The elderly is vulnerable to not only malnutrition but also hypofunction of all organs and a variety of chronic diseases such as sarcopenia, osteoporosis, gastrointestinal dysfunction, and mental problems. As the major macronutrient, food protein plays an important role in elderly health and well-being. In this chapter, the function of protein and peptide in elderly health as well as their effects on preventing aging-related disease is reviewed.

      PubDate: 2018-04-16T01:56:04Z
      DOI: 10.1016/bs.apcsb.2018.03.003
  • Therapeutic Monoclonal Antibodies Delivery for the Glioblastoma Treatment
    • Authors: Flávia Sousa; Rui P. Moura; Elias Moreira; Cláudia Martins; Bruno Sarmento
      Abstract: Publication date: Available online 30 March 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Flávia Sousa, Rui P. Moura, Elias Moreira, Cláudia Martins, Bruno Sarmento
      Glioblastoma multiforme (GBM) is the most common and challenging primary malignant brain tumor, being the median overall survival between 10 and 14 months due to its invasive characteristics. GBM treatment is mainly based on the maximal surgical resection and radiotherapy associated to chemotherapy. Monoclonal antibodies (mAbs) have been used in chemotherapy protocols for GBM treatment in order to improve immunotherapy and antiangiogenic processes. High specificity and affinity of mAbs for biological targets make them highly used for brain tumor therapy. Specifically, antiangiogenic mAbs have been wisely indicated in chemotherapy protocols because GBM is the most vascularized tumors in humans with high expression of cytokines. However, mAb-based therapy is not that effective due to the aggressive spread of the tumor associated to the difficulty in the access of mAb into the brain (due to the blood–brain barrier). For that reason, nanobiotechnology has played an important role in the treatment of several tumors, mainly in the tumors of difficult access, such as GBM. In this chapter will be discussed strategies related with nanobiotechnology applied to the mAb delivery and how these therapeutics can improve the GBM treatment and life quality of the patient.

      PubDate: 2018-04-16T01:56:04Z
      DOI: 10.1016/bs.apcsb.2018.03.001
  • Computational Methods to Discover Compounds for the Treatment of Chagas
    • Authors: Eduardo M. Cortés-Ruiz; Oscar Palomino-Hernández; Karla Daniela Rodríguez-Hernández; Bertha Espinoza; José L. Medina-Franco
      Abstract: Publication date: Available online 16 March 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Eduardo M. Cortés-Ruiz, Oscar Palomino-Hernández, Karla Daniela Rodríguez-Hernández, Bertha Espinoza, José L. Medina-Franco
      Infectious diseases continue to be a major public health. Among these diseases, American trypanosomiasis or Chagas disease (CD) is a major cause of morbidity and death for millions of people in Latin America. The two drugs currently available for the treatment of CD have poor efficacy and major side effects. Thus, there is a pressing need to develop safe and effective drugs against this disease. Herein we review the diversity and coverage of chemical space of compounds tested as inhibitors of Trypanosoma cruzi, a parasite causing CD. We also review major molecular targets currently pursued to kill the parasite and recent computational approaches to identify inhibitors for such targets.

      PubDate: 2018-03-19T17:56:45Z
      DOI: 10.1016/bs.apcsb.2018.03.005
  • Computational Methods for Epigenetic Drug Discovery: A Focus on Activity
           Landscape Modeling
    • Authors: J. Jesús Naveja; C. Iluhí Oviedo-Osornio; José L. Medina-Franco
      Abstract: Publication date: Available online 5 March 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): J. Jesús Naveja, C. Iluhí Oviedo-Osornio, José L. Medina-Franco
      Epigenetic drug discovery is an emerging strategy against several chronic and complex diseases. The increased interest in epigenetics has boosted the development and maintenance of large information on structure–epigenetic activity relationships for several epigenetic targets. In turn, such large databases—many in the public domain—are a rich source of information to explore their structure–activity relationships (SARs). Herein, we conducted a large-scale analysis of the SAR of epigenetic targets using the concept of activity landscape modeling. A comprehensive quantitative analysis and a novel visual representation of the epigenetic activity landscape enabled the rapid identification of regions of targets with continuous and discontinuous SAR. This information led to the identification of epigenetic targets for which it is anticipated an easier or a more difficult drug-discovery program using conventional hit-to-lead approaches. The insights of this work also enabled the identification of specific structural changes associated with a large shift in biological activity. To the best of our knowledge, this work represents the largest comprehensive SAR analysis of several epigenetic targets and contributes to the better understanding of the epigenetic activity landscape.

      PubDate: 2018-03-07T09:46:59Z
      DOI: 10.1016/bs.apcsb.2018.01.001
  • In Silico Tools and Databases for Designing Peptide-Based Vaccine and
    • Authors: Salman Sadullah Usmani; Rajesh Kumar; Sherry Bhalla; Vinod Kumar; Gajendra P.S. Raghava
      Abstract: Publication date: Available online 5 March 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Salman Sadullah Usmani, Rajesh Kumar, Sherry Bhalla, Vinod Kumar, Gajendra P.S. Raghava
      The prolonged conventional approaches of drug screening and vaccine designing prerequisite patience, vigorous effort, outrageous cost as well as additional manpower. Screening and experimentally validating thousands of molecules for a specific therapeutic property never proved to be an easy task. Similarly, traditional way of vaccination includes administration of either whole or attenuated pathogen, which raises toxicity and safety issues. Emergence of sequencing and recombinant DNA technology led to the epitope-based advanced vaccination concept, i.e., small peptides (epitope) can stimulate specific immune response. Advent of bioinformatics proved to be an adjunct in vaccine and drug designing. Genomic study of pathogens aid to identify and analyze the protective epitope. A number of in silico tools have been developed to design immunotherapy as well as peptide-based drugs in the last two decades. These tools proved to be a catalyst in drug and vaccine designing. This review solicits therapeutic peptide databases as well as in silico tools developed for designing peptide-based vaccine and drugs.

      PubDate: 2018-03-07T09:46:59Z
      DOI: 10.1016/bs.apcsb.2018.01.006
  • Peptide Derivatives of Erythropoietin in the Treatment of
           Neuroinflammation and Neurodegeneration
    • Authors: Ilkcan Ercan; Kemal Ugur Tufekci; Ezgi Karaca; Sermin Genc; Kursad Genc
      Abstract: Publication date: Available online 28 February 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Ilkcan Ercan, Kemal Ugur Tufekci, Ezgi Karaca, Sermin Genc, Kursad Genc
      During the past 35 years, recombinant DNA technology has allowed the production of a wide range of hematopoietic and neurotrophic growth factors including erythropoietin (EPO). These have emerged as promising protein drugs in various human diseases. Accumulated evidences have recently demonstrated the neuroprotective effect of EPO in preclinical models of acute and chronic degenerative disorders. Nevertheless, tissue protective effect of EPO could not be translated to the clinical trials because of common lethal thromboembolic events, erythropoiesis and hypertension. Although chemically modified nonerythropoietic analogs of EPO bypass these side effects, high expense, development of antidrug antibodies, and promotion of tumorigenicity are still concern especially in long-term use. As an alternative, nonerythropoietic EPO mimetic peptides can be used as candidate drugs with their high potency and selectivity, easy production, low cost, and immunogenicity properties. Recent experimental studies suggest that these peptides prevent ischemic brain injury and neuroinflammation. The results of clinical trial in patients with neuropathic pain are also promising. Herein, we summarize these studies and review advanced experimental and in silico methods in peptide drug discovery.

      PubDate: 2018-03-07T09:46:59Z
      DOI: 10.1016/bs.apcsb.2018.01.007
  • Smart Cell-Penetrating Peptide-Based Techniques for Intracellular Delivery
           of Therapeutic Macromolecules
    • Authors: Yang He; Feng Li; Yongzhuo Huang
      Abstract: Publication date: Available online 26 February 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Yang He, Feng Li, Yongzhuo Huang
      Many therapeutic macromolecules must enter cells to take their action. However, their treatment outcomes are often hampered by their poor transportation into target cells. Therefore, efficient intracellular delivery of these macromolecules is critical for improving their therapeutic efficacy. Cell-penetrating peptide (CPP)-based approaches are one of the most efficient methods for intracellular delivery of macromolecular therapeutics. Nevertheless, poor specificity is a significant concern for systemic administrated CPP-based delivery systems. This chapter will review recent advances in CPP-mediated macromolecule delivery with a focus on various smart strategies which not only enhance the intracellular delivery but also improve the targeting specificity.

      PubDate: 2018-03-07T09:46:59Z
      DOI: 10.1016/bs.apcsb.2018.01.004
  • Dynamical Behavior of Somatostatin-14 and Its Cyclic Analogues as Analyzed
           in Bulk and on Plasmonic Silver Nanoparticles
    • Authors: Belén Hernández; Yves-Marie Coïc; Eduardo López-Tobar; Santiago Sanchez-Cortes; Bruno Baron; Fernando Pflüger; Sergei G. Kruglik; Régis Cohen; Mahmoud Ghomi
      Abstract: Publication date: Available online 23 February 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Belén Hernández, Yves-Marie Coïc, Eduardo López-Tobar, Santiago Sanchez-Cortes, Bruno Baron, Fernando Pflüger, Sergei G. Kruglik, Régis Cohen, Mahmoud Ghomi
      Primarily known as the inhibitor of growth hormone release, the role of somatostatin in many other inhibiting activities upon binding to its five G-protein-coupled receptors has been elucidated. Because of the short half-life of somatostatin, a number of synthetic analogues were elaborated for this peptide hormone. Herein, after recalling the main somatostatin therapeutic interests, we present the dynamical behavior of somatostatin-14 and its two currently used synthetic cyclic analogues, octreotide and pasireotide. Physical techniques, such as fluorescence, UV–visible absorption, circular dichroism, Raman spectroscopy, surface-enhanced Raman spectroscopy, and transmission electron microscopy, were jointly used in order to get information on the solution structural features, as well as on the anchoring sites of the three peptides on silver colloids. While somatostatin-14 adopts a rather unordered chain within the submillimolar concentration range, its cyclic analogues were revealed to be ordered, i.e., stabilized either in a type-II′ β-turn (octreotide) or in a face-to-face γ-turn/type-I β-turn (pasireotide) structure. Nevertheless, a progressive structuring trend was observed in somatostatin-14 upon increasing concentration to the millimolar range. Because of their cationic character, the three peptides have revealed their capability to bind onto negatively charged silver nanoparticles. The high affinity of the peptides toward metallic particles seems to be extremely promising for the elaboration of somatostatin-based functionalized plasmonic nanoparticles that can be used in diagnosis, drug delivery, and therapy.

      PubDate: 2018-02-26T12:21:26Z
      DOI: 10.1016/bs.apcsb.2018.01.002
  • The Structure/Function Relationship in Antimicrobial Peptides: What Can we
           Obtain From Structural Data'
    • Authors: Marlon H. Cardoso; Karen G.N. Oshiro; Samilla B. Rezende; Elizabete S. Cândido; Octávio L. Franco
      Abstract: Publication date: Available online 23 February 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Marlon H. Cardoso, Karen G.N. Oshiro, Samilla B. Rezende, Elizabete S. Cândido, Octávio L. Franco
      Antimicrobial peptides (AMPs) have been widely isolated from most organisms in nature. This class of antimicrobials may undergo changes in their sequence for improved physicochemical properties, including charge, hydrophobicity, and hydrophobic moment. It is known that such properties may be directly associated with AMPs’ structural arrangements and, consequently, could interfere in their modes of action against microorganisms. In this scenario, biophysical methodologies, such as nuclear magnetic resonance spectroscopy, X-ray crystallography, and cryo-electron microscopy, allied to in silico approaches, including molecular modeling, docking, and dynamics nowadays represent an enormous first step for the structural elucidation of AMPs, leading to further structure–function annotation. In this context, this chapter will focus on the main atomic-level experimental and computational tools used for the structural elucidation of AMPs that have assisted in the investigation of their functions.

      PubDate: 2018-02-26T12:21:26Z
      DOI: 10.1016/bs.apcsb.2018.01.008
  • Transglutaminase and Sialyltransferase Enzymatic Approaches for Polymer
           Conjugation to Proteins
    • Authors: Katia Maso; Antonella Grigoletto; Gianfranco Pasut
      Abstract: Publication date: Available online 12 February 2018
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Katia Maso, Antonella Grigoletto, Gianfranco Pasut
      Proteins hold a central role in medicine and biology, also confirmed by the several therapeutic applications based on biologic drugs. Such therapies are of great relevance thanks to high potency and safety of proteins. Nevertheless, many proteins as therapeutics might present issues like fast kidney clearance, rapid enzymatic degradation, or immunogenicity. Such defects implicate frequent administrations or administrations at high doses of the therapeutics, thus yielding or exacerbating potential side effects. A successful technology for improving the clinical profiles of proteins is the conjugation of polymers to the protein surface. The design of a protein–polymer conjugate presents critical aspects that determine the efficacy and safety of the final product. The control over stoichiometry and conjugation site is a strict criterion on which researchers have been intensively focused during the years, in order to obtain homogeneous and batch-to-batch reproducible products. An innovative site-specific conjugation strategy relies on the use of enzymes as tools to mediate polymer conjugation. Enzymatic approaches are attractive because they allow site-selective polymer conjugation at specific protein amino acids. In these reactions, the polymer is a substrate analog that replaces the native substrate. Furthermore, enzymes can count other advantages such as high yields of conversion and physiological conditions of reaction. This chapter provides a meaningful description of protein–polymer conjugation through transglutaminase-mediated and sialyltransferase-mediated enzymatic strategies, reporting the mechanism of action and some relevant examples.

      PubDate: 2018-02-17T08:41:49Z
      DOI: 10.1016/bs.apcsb.2018.01.003
  • Chapter Six Enzymology of Microbial Dimethylsulfoniopropionate Catabolism
    • Authors: Mishtu Dey
      Pages: 195 - 222
      Abstract: Publication date: 2017
      Source:Advances in Protein Chemistry and Structural Biology, Volume 109
      Author(s): Mishtu Dey
      The biochemistry of dimethylsulfoniopropionate (DMSP) catabolism is reviewed. The microbes that catalyze the reactions central to DMSP catabolic pathways are described, and the focus is on the enzymology of the process. Approximately 109 tons of DMSP is released annually by marine eukaryotes as an osmolyte. A vast majority of DMSP is assimilated by bacteria through either a demethylation or lyase pathways, producing either the methane thiol or the volatile dimethylsulfide (DMS), respectively. Enzymatic breakdown of DMSP generates ~107 tons of DMS annually, which may have impact on global climate. DMS also acts as a chemoattractant for zooplanktons and seabirds. Both DMSP and DMS play a key role in the global sulfur cycle and are key nutrients for marine microbial growth. Important enzymes in the biochemical pathways of DMSP catabolism are covered in this review, with a focus on the latest developments in their mechanism.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.05.001
      Issue No: Vol. 109 (2017)
  • Defining Pharmacological Targets by Analysis of Virus–Host Protein
    • Authors: Manuel Llano; Mario A. Peña-Hernandez
      Abstract: Publication date: Available online 18 December 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Manuel Llano, Mario A. Peña-Hernandez
      Viruses are obligate parasites that depend on cellular factors for replication. Pharmacological inhibition of essential viral proteins, mostly enzymes, is an effective therapeutic alternative in the absence of effective vaccines. However, this strategy commonly encounters drug resistance mechanisms that allow these pathogens to evade control. Due to the dependency on host factors for viral replication, pharmacological disruption of the host-pathogen protein–protein interactions (PPIs) is an important therapeutic alternative to block viral replication. In this review we discuss salient aspects of PPIs implicated in viral replication and advances in the development of small molecules that inhibit viral replication through antagonism of these interactions.

      PubDate: 2017-12-21T22:14:01Z
      DOI: 10.1016/bs.apcsb.2017.11.001
  • Human Interactomics: Comparative Analysis of Different Protein Interaction
           Resources and Construction of a Cancer Protein–Drug Bipartite Network
    • Authors: Javier De Las Rivas; Diego Alonso-López; Mónica M. Arroyo
      Abstract: Publication date: Available online 6 November 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Javier De Las Rivas, Diego Alonso-López, Mónica M. Arroyo
      Unraveling the protein interaction wiring that occurs in human cells as a scaffold of biological processes requires the identification of all elements that constitute such molecular interaction networks. Proteome-wide experimental studies and bioinformatic comprehensive efforts have provided reliable and updated compendiums of the human protein interactome. In this work, we present a current view of available databases of human protein–protein interactions (PPIs) that allow building protein interaction networks. We also investigate human proteins as targets of specific drugs to analyze how chemicals interact with different target proteins, placing also the study in a network relational space. Hence, we undertake a description of several major drug–target resources to provide a present perspective of the associations between human proteins and specific chemicals. The identification of molecular targets for specific drugs is a critical step to improve disease therapy. As different diseases have different biomolecular scenarios, we addressed the identification of drug-targeted genes focusing our investigations on cancer and cancer genes. So, a description of resources that provide curated compendiums of human cancer genes is presented. Cancer is a complex disease where multiple genetic changes rewire cellular networks during carcinogenesis. This indicates that cancer drug therapy needs the implementation of network-driven studies to reveal multiplex interactions between cancer genes and drugs. To make progress in this direction, in the last part of this work we provide a bipartite network of cancer genes and their drugs shown in a graph landscape that disclose the existence of specific drug–target modules.

      PubDate: 2017-11-11T22:41:41Z
      DOI: 10.1016/bs.apcsb.2017.09.002
  • Targeting Protein–Protein Interactions in the
           Ubiquitin–Proteasome Pathway
    • Authors: Maria Gaczynska; Pawel A. Osmulski
      Abstract: Publication date: Available online 18 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Maria Gaczynska, Pawel A. Osmulski
      The ubiquitin–proteasome pathway (UPP) is a major venue for controlled intracellular protein degradation in Eukaryota. The machinery of several hundred proteins is involved in recognizing, tagging, transporting, and cleaving proteins, all in a highly regulated manner. Short-lived transcription factors, misfolded translation products, stress-damaged polypeptides, or worn-out long-lived proteins, all can be found among the substrates of UPP. Carefully choreographed protein–protein interactions (PPI) are involved in each step of the pathway. For many of the steps small-molecule inhibitors have been identified and often they directly or indirectly target PPI. The inhibitors may destabilize intracellular proteostasis and trigger apoptosis. So far this is the most explored option used as an anticancer strategy. Alternatively, substrate-specific polyubiquitination may be regulated for a precise intervention aimed at a particular metabolic pathway. This very attractive opportunity is moving close to clinical application. The best known drug target in UPP is the proteasome: the end point of the journey of a protein destined for degradation. The proteasome alone is a perfect object to study the mechanisms and roles of PPI on many levels. This giant protease is built from multisubunit modules and additionally utilizes a service from transient protein ligands, for example, delivering substrates. An elaborate set of PPI within the highest-order proteasome assembly is involved in substrate recognition and processing. Below we will outline PPI involved in the UPP and discuss the growing prospects for their utilization in pharmacological interventions.

      PubDate: 2017-10-22T10:02:24Z
      DOI: 10.1016/bs.apcsb.2017.09.001
  • Investigating the Influence of Hotspot Mutations in Protein–Protein
           Interaction of IDH1 Homodimer Protein: A Computational Approach
    • Authors: D. Thirumal Kumar; P. Sneha; Jennifer Uppin; S. Usha; C. George Priya Doss
      Abstract: Publication date: Available online 14 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): D. Thirumal Kumar, P. Sneha, Jennifer Uppin, S. Usha, C. George Priya Doss
      Protein–protein interaction (PPI) helps in maintaining the cellular homeostasis. In particular, the homodimeric proteins play a crucial role as cell regulators. Studying the critical functions of each PPI on the living system is very challenging. The mutations in the PPIs have given birth to various diseases including many types of cancers and it has soon become the target for drug discovery. The mutations in IDH1, an asymmetric homodimer in the cytoplasm, leads to various diseases including gliomas. In this study, we have used extensive computational approaches to identify the impact of missense mutations (R132C, R132G, R132H, R132L, R132S, and V178I) occurring in the interacting region of the IDH1 homodimer. By in silico pathogenicity analysis, all the mutations occurring at the position 132 and 178 were found to be pathogenic and neutral. Furthermore, the mutants R132C and R132G were found to be responsible for increasing the stability, whereas the mutants R132H, R132L, and R132S were found to be responsible for the decrease in stability by stability analysis. R132H, R132L, and R132S mutants exhibited higher destabilization when compared to the structures of R132C and R132G mutants by molecular docking and molecular dynamics analysis.

      PubDate: 2017-10-14T02:06:25Z
      DOI: 10.1016/bs.apcsb.2017.08.002
  • Computational Resources for Predicting Protein–Protein Interactions
    • Authors: Himani Tanwar; C. George Priya Doss
      Abstract: Publication date: Available online 12 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Himani Tanwar, C. George Priya Doss
      Proteins are the essential building blocks and functional components of a cell. They account for the vital functions of an organism. Proteins interact with each other and form protein interaction networks. These protein interactions play a major role in all the biological processes and pathways. The previous methods of predicting protein interactions were experimental which focused on a small set of proteins or a particular protein. However, these experimental approaches are low-throughput as they are time-consuming and require a significant amount of human effort. This led to the development of computational techniques that uses high-throughput experimental data for analyzing protein–protein interactions. The main purpose of this review is to provide an overview on the computational advancements and tools for the prediction of protein interactions. The major databases for the deposition of these interactions are also described. The advantages, as well as the specific limitations of these tools, are highlighted which will shed light on the computational aspects that can help the biologist and researchers in their research.

      PubDate: 2017-10-14T02:06:25Z
      DOI: 10.1016/bs.apcsb.2017.07.006
  • Probing the Protein–Protein Interaction Network of Proteins Causing
           Maturity Onset Diabetes of the Young
    • Authors: P. Sneha; D. Thirumal Kumar; Jose Lijo; M. Megha; R. Siva; C. George Priya Doss
      Abstract: Publication date: Available online 10 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): P. Sneha, D. Thirumal Kumar, Jose Lijo, M. Megha, R. Siva, C. George Priya Doss
      Protein–protein interactions (PPIs) play vital roles in various cellular pathways. Most of the proteins perform their responsibilities by interacting with an enormous number of proteins. Understanding these interactions of the proteins and their interacting partners has shed light toward the field of drug discovery. Also, PPIs enable us to understand the functions of a protein by understanding their interacting partners. Consequently, in the current study, PPI network of the proteins causing MODY (Maturity Onset Diabetes of the Young) was drawn, and their correlation in causing a disease condition was marked. MODY is a monogenic type of diabetes caused by autosomal dominant inheritance. Extensive research on transcription factor and their corresponding genetic pathways have been studied over the last three decades, yet, very little is understood about the molecular modalities of highly dynamic interactions between transcription factors, genomic DNA, and the protein partners. The current study also reveals the interacting patterns of the various transcription factors. Consequently, in the current work, we have devised a PPI analysis to understand the plausible pathway through which the protein leads to a deformity in glucose uptake.

      PubDate: 2017-10-14T02:06:25Z
      DOI: 10.1016/bs.apcsb.2017.07.004
  • Multifaceted Nucleolin Protein and Its Molecular Partners in Oncogenesis
    • Authors: Iva Ugrinova; Maria Petrova Mounira Chalabi-Dchar Philippe Bouvet
      Abstract: Publication date: Available online 6 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Iva Ugrinova, Maria Petrova, Mounira Chalabi-Dchar, Philippe Bouvet
      Discovered in 1973, nucleolin is one of the most abundant phosphoproteins of the nucleolus. The ability of nucleolin to be involved in many cellular processes is probably related to its structural organization and its capability to form many different interactions with other proteins. Many functions of nucleolin affect cellular processes involved in oncogenesis—for instance: in ribosome biogenesis; in DNA repair, remodeling, and genome stability; in cell division and cell survival; in chemokine and growth factor signaling pathways; in angiogenesis and lymphangiogenesis; in epithelial–mesenchymal transition; and in stemness. In this review, we will describe the different functions of nucleolin in oncogenesis through its interaction with other proteins.

      PubDate: 2017-10-08T20:41:03Z
  • Homo- and Heterodimerization of Proteins in Cell Signaling: Inhibition and
           Drug Design
    • Authors: Sitanshu Singh; Seetharama Jois
      Abstract: Publication date: Available online 6 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Sitanshu S. Singh, Seetharama D. Jois
      Protein dimerization controls many physiological processes in the body. Proteins form homo-, hetero-, or oligomerization in the cellular environment to regulate the cellular processes. Any deregulation of these processes may result in a disease state. Protein–protein interactions (PPIs) can be inhibited by antibodies, small molecules, or peptides, and inhibition of PPI has therapeutic value. PPI drug discovery research has steadily increased in the last decade, and a few PPI inhibitors have already reached the pharmaceutical market. Several PPI inhibitors are in clinical trials. With advancements in structural and molecular biology methods, several methods are now available to study protein homo- and heterodimerization and their inhibition by drug-like molecules. Recently developed methods to study PPI such as proximity ligation assay and enzyme-fragment complementation assay that detect the PPI in the cellular environment are described with examples. At present, the methods used to design PPI inhibitors can be classified into three major groups: (1) structure-based drug design, (2) high-throughput screening, and (3) fragment-based drug design. In this chapter, we have described some of the experimental methods to study PPIs and their inhibition. Examples of homo- and heterodimers of proteins, their structural and functional aspects, and some of the inhibitors that have clinical importance are discussed. The design of PPI inhibitors of epidermal growth factor receptor heterodimers and CD2–CD58 is discussed in detail.

      PubDate: 2017-10-08T20:41:03Z
  • Analysis of Protein Interactions by Surface Plasmon Resonance
    • Authors: Dennis G. Drescher; Dakshnamurthy Selvakumar; Marian J. Drescher
      Abstract: Publication date: Available online 12 September 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Dennis G. Drescher, Dakshnamurthy Selvakumar, Marian J. Drescher
      Surface plasmon resonance is an optical technique that is utilized for detecting molecular interactions, such as interactions that occur between proteins or other classes of molecules. Binding of a mobile molecule (analyte) to a molecule immobilized on a thin metal film (ligand) changes the refractive index of the film. The angle of extinction of light that is completely reflected after polarized light impinges upon the film, is altered and monitored as a change in detector position for a dip in reflected intensity (the surface plasmon resonance phenomenon). Because the method strictly detects mass, there is no need to label the interacting components, thus eliminating possible changes of their molecular properties. In this chapter, we review essential SPR methodology and present applications to basic science and human disease.

      PubDate: 2017-09-18T04:43:08Z
      DOI: 10.1016/bs.apcsb.2017.07.003
  • Using TR-FRET to Investigate Protein–Protein Interactions: A Case Study
           of PXR-Coregulator Interaction
    • Authors: Wenwei Lin; Taosheng Chen
      Abstract: Publication date: Available online 31 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Wenwei Lin, Taosheng Chen
      Time-resolved fluorescence resonance energy transfer (TR-FRET) protein–protein interaction assays, especially in the format of receptor coregulator (coactivator and corepressor) recruitment/repression assays, have been widely used in nuclear receptor research to characterize the modes of action, efficacies, and binding affinities of ligands (including their properties as agonists, antagonists, and inverse agonists). However, there has been only limited progress in using this assay format for pregnane X receptor (PXR). In this chapter, we discuss TR-FRET protein–protein interaction assays and focus on a novel PXR TR-FRET coactivator interaction assay that we have developed based on a PXR coactivator cocrystal study. This new PXR TR-FRET coactivator interaction assay can characterize the binding affinities of PXR ligands and also differentiate antagonists from agonists. This assay is very robust, with the signal remaining stable over a long incubation time (up to 300min has been tested). It can tolerate high concentrations of DMSO (up to 5%) and has a high signal-to-noise ratio (six under typical assay conditions). This newly developed PXR TR-FRET coactivator interaction assay has potential application in high-throughput screening to identify and characterize novel PXR agonists and antagonists.

      PubDate: 2017-09-05T23:52:57Z
      DOI: 10.1016/bs.apcsb.2017.06.001
  • Structural Prediction of Protein–Protein Interactions by Docking:
           Application to Biomedical Problems
    • Authors: Didier Barradas-Bautista; Mireia Rosell; Chiara Pallara; Juan Fernández-Recio
      Abstract: Publication date: Available online 31 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Didier Barradas-Bautista, Mireia Rosell, Chiara Pallara, Juan Fernández-Recio
      A huge amount of genetic information is available thanks to the recent advances in sequencing technologies and the larger computational capabilities, but the interpretation of such genetic data at phenotypic level remains elusive. One of the reasons is that proteins are not acting alone, but are specifically interacting with other proteins and biomolecules, forming intricate interaction networks that are essential for the majority of cell processes and pathological conditions. Thus, characterizing such interaction networks is an important step in understanding how information flows from gene to phenotype. Indeed, structural characterization of protein–protein interactions at atomic resolution has many applications in biomedicine, from diagnosis and vaccine design, to drug discovery. However, despite the advances of experimental structural determination, the number of interactions for which there is available structural data is still very small. In this context, a complementary approach is computational modeling of protein interactions by docking, which is usually composed of two major phases: (i) sampling of the possible binding modes between the interacting molecules and (ii) scoring for the identification of the correct orientations. In addition, prediction of interface and hot-spot residues is very useful in order to guide and interpret mutagenesis experiments, as well as to understand functional and mechanistic aspects of the interaction. Computational docking is already being applied to specific biomedical problems within the context of personalized medicine, for instance, helping to interpret pathological mutations involved in protein–protein interactions, or providing modeled structural data for drug discovery targeting protein–protein interactions.

      PubDate: 2017-09-05T23:52:57Z
      DOI: 10.1016/bs.apcsb.2017.06.003
  • Development of Protein–Protein Interaction Inhibitors for the
           Treatment of Infectious Diseases
    • Authors: Andrew F. Voter; James L. Keck
      Abstract: Publication date: Available online 24 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Andrew F. Voter, James L. Keck
      Protein–protein interaction (PPI) inhibitors are a rapidly expanding class of therapeutics. Recent advances in our understanding of PPIs and success of early examples of PPI inhibitors demonstrate the feasibility of targeting PPIs. This review summarizes the techniques used for the discovery and optimization of a diverse set PPI inhibitors, focusing on the development of PPI inhibitors as new antibacterial and antiviral agents. We close with a summary of the advances responsible for making PPI inhibitors realistic targets for therapeutic intervention and brief outlook of the field.

      PubDate: 2017-08-29T21:00:12Z
      DOI: 10.1016/bs.apcsb.2017.07.005
  • Subcellular Targeting of Nitric Oxide Synthases Mediated by Their
           N-Terminal Motifs
    • Authors: Carlos Costas-Insua; Javier Merino-Gracia; Clara Aicart-Ramos; Ignacio Rodríguez-Crespo
      Abstract: Publication date: Available online 24 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Carlos Costas-Insua, Javier Merino-Gracia, Clara Aicart-Ramos, Ignacio Rodríguez-Crespo
      From a catalytic point of view, the three mammalian nitric oxide synthases (NOSs) function in an almost identical way. The N-terminal oxygenase domain catalyzes the conversion of l-arginine to l-citrulline plus ·NO in two sequential oxidation steps. Once l-arginine binds to the active site positioned above the heme moiety, two consecutive monooxygenation reactions take place. In the first step, l-arginine is hydroxylated to make Nω-hydroxy-l-arginine in a process that requires 1 molecule of NADPH and 1 molecule of O2 per mol of l-arginine reacted. In the second step, Nω-hydroxy-l-arginine, never leaving the active site, is oxidized to ·NO plus l-citrulline and 1 molecule of O2 and 0.5 molecules of NADPH are consumed. Since nitric oxide is an important signaling molecule that participates in a number of biological processes, including neurotransmission, vasodilation, and immune response, synthesis and release of ·NO in vivo must be exquisitely regulated both in time and in space. Hence, NOSs have evolved introducing in their amino acid sequences subcellular targeting motifs, most of them located at their N-termini. Deletion studies performed on recombinant, purified NOSs have revealed that part of the N-terminus of all three NOS can be eliminated with the resulting mutant enzymes still being catalytically active. Likewise, NOS isoforms lacking part of their N-terminus when transfected in cells render mislocalized, active proteins. In this review we will comment on the current knowledge of these subcellular targeting signals present in nNOS, iNOS, and eNOS.

      PubDate: 2017-08-29T21:00:12Z
      DOI: 10.1016/bs.apcsb.2017.07.002
  • Targeting the Architecture of Deregulated Protein Complexes in Cancer
    • Authors: Eduard Stefan; Jakob Troppmair; Klaus Bister
      Abstract: Publication date: Available online 18 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Eduard Stefan, Jakob Troppmair, Klaus Bister
      The architectures of central signaling hubs are precisely organized by static and dynamic protein–protein interactions (PPIs). Upon deregulation, these PPI platforms are capable to propagate or initiate pathophysiological signaling events. This causes the acquisition of molecular features contributing to the etiology or progression of many diseases, including cancer, where deregulated molecular interactions of signaling proteins have been best studied. The reasons for PPI-dependent reprogramming of cancer-initiating cells are manifold; in many cases, mutations perturb PPIs, enzyme activities, protein abundance, or protein localization. Consequently, the pharmaceutical targeting of PPIs promises to be of remarkable therapeutic value. For this review we have selected three key players of oncogenic signaling which are differently affected by PPI deregulation: two (the small G proteins of the RAS family and the transcription factor MYC) are considered “undruggable” using classical drug discovery approaches and in the case of the third protein discussed here, PKA, standard kinase inhibitors, may be unsuitable in the clinic. These circumstances require alternative strategies, which may lie in pharmaceutical drug interference of critical PPIs accountable for oncogenic signaling.

      PubDate: 2017-08-18T16:55:48Z
      DOI: 10.1016/bs.apcsb.2017.07.001
  • Protein–Protein Interaction Modulators for Epigenetic Therapies
    • Authors: Bárbara I. Díaz-Eufracio; J. Jesús Naveja; José L. Medina-Franco
      Abstract: Publication date: Available online 25 July 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Bárbara I. Díaz-Eufracio, J. Jesús Naveja, José L. Medina-Franco
      Targeting protein–protein interactions (PPIs) is becoming an attractive approach for drug discovery. This is particularly true for difficult or emerging targets, such as epitargets that may be elusive to drugs that fall into the traditional chemical space. The chemical nature of the PPIs makes attractive the use of peptides or peptidomimetics to selectively modulate such interactions. Despite the fact peptide-based drug discovery has been challenging, the use of peptides as leads compounds for drug discovery is still a valid strategy. This chapter discusses the current status of PPIs in epigenetic drug discovery. A special emphasis is made on peptides and peptide-like compounds as potential drug candidates.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.06.002
  • Intrinsic Disorder, Protein–Protein Interactions, and Disease
    • Authors: Vladimir N. Uversky
      Abstract: Publication date: Available online 24 July 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Vladimir N. Uversky
      It is recognized now that biologically active proteins without stable tertiary structure (known as intrinsically disordered proteins, IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are important players found in any given proteome. These IDPs/IDPRs possess functions that complement functional repertoire of their ordered counterparts, being commonly related to recognition, as well as control and regulation of various signaling pathways. They are interaction masters, being able to utilize a wide spectrum of interaction mechanisms, ranging from induced folding to formation of fuzzy complexes where significant levels of disorder are preserved, to polyvalent stochastic interactions playing crucial roles in the liquid–liquid phase transitions leading to the formation of proteinaceous membrane-less organelles. IDPs/IDPRs are tightly controlled themselves via various means, including alternative splicing, precisely controlled expression and degradation, binding to specific partners, and posttranslational modifications. Distortions in the regulation and control of IDPs/IDPRs, as well as their aberrant interactivity are commonly associated with various human diseases. This review presents some aspects of the intrinsic disorder-based functionality and dysfunctionality, paying special attention to the normal and pathological protein–protein interactions.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.06.005
  • Targeting Intramembrane Protein–Protein Interactions: Novel Therapeutic
           Strategy of Millions Years Old
    • Authors: Alexander B. Sigalov
      Abstract: Publication date: Available online 24 July 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Alexander B. Sigalov
      Intramembrane protein–protein interactions (PPIs) are involved in transmembrane signal transduction mediated by cell surface receptors and play an important role in health and disease. Recently, receptor-specific modulatory peptides rationally designed using a general platform of transmembrane signaling, the signaling chain homooligomerization (SCHOOL) model, have been proposed to therapeutically target these interactions in a variety of serious diseases with unmet needs including cancer, sepsis, arthritis, retinopathy, and thrombosis. These peptide drug candidates use ligand-independent mechanisms of action (SCHOOL mechanisms) and demonstrate potent efficacy in vitro and in vivo. Recent studies surprisingly revealed that in order to modify and/or escape the host immune response, human viruses use similar mechanisms and modulate cell surface receptors by targeting intramembrane PPIs in a ligand-independent manner. Here, I review these intriguing mechanistic similarities and discuss how the viral strategies optimized over a billion years of the coevolution of viruses and their hosts can help to revolutionize drug discovery science and develop new, disruptive therapies. Examples are given.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.06.004
  • A Paradigm for CH Bond Cleavage: Structural and Functional Aspects of
           Transition State Stabilization by Mandelate Racemase
    • Authors: Stephen L. Bearne; Martin St. Maurice
      Abstract: Publication date: Available online 9 June 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Stephen L. Bearne, Martin St. Maurice
      Mandelate racemase (MR) from Pseudomonas putida catalyzes the Mg2+-dependent, 1,1-proton transfer reaction that racemizes (R)- and (S)-mandelate. MR shares a partial reaction (i.e., the metal ion-assisted, Brønsted base-catalyzed proton abstraction of the α-proton of carboxylic acid substrates) and structural features ((β/α)7β-barrel and N-terminal α + β capping domains) with a vast group of homologous, yet functionally diverse, enzymes in the enolase superfamily. Mechanistic and structural studies have developed this enzyme into a paradigm for understanding how enzymes such as those of the enolase superfamily overcome kinetic and thermodynamic barriers to catalyze the abstraction of an α-proton from a carbon acid substrate with a relatively high pK a value. Structural studies on MR bound to intermediate/transition state analogues have delineated those structural features that MR uses to stabilize transition states and enhance reaction rates of proton abstraction. Kinetic, site-directed mutagenesis, and structural studies have also revealed that the phenyl ring of the substrate migrates through the hydrophobic cavity within the active site during catalysis and that the Brønsted acid–base catalysts (Lys 166 and His 297) may be utilized as binding determinants for inhibitor recognition. In addition, structural studies on the adduct formed from the irreversible inhibition of MR by 3-hydroxypyruvate revealed that MR can form and deprotonate a Schiff-base with 3-hydroxypyruvate to yield an enol(ate)-aldehyde adduct, suggesting a possible evolutionary link between MR and the Schiff-base forming aldolases. As the archetype of the enolase superfamily, mechanistic and structural studies on MR will continue to enhance our understanding of enzyme catalysis and furnish insights into the evolution of enzyme function.

      PubDate: 2017-06-13T07:14:51Z
      DOI: 10.1016/bs.apcsb.2017.04.007
  • Sortase Transpeptidases: Structural Biology and Catalytic Mechanism
    • Authors: Alex W. Jacobitz; Michele D. Kattke; Jeff Wereszczynski; Robert T. Clubb
      Abstract: Publication date: Available online 5 June 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Alex W. Jacobitz, Michele D. Kattke, Jeff Wereszczynski, Robert T. Clubb
      Gram-positive bacteria use sortase cysteine transpeptidase enzymes to covalently attach proteins to their cell wall and to assemble pili. In pathogenic bacteria sortases are potential drug targets, as many of the proteins that they display on the microbial surface play key roles in the infection process. Moreover, the Staphylococcus aureus Sortase A (SaSrtA) enzyme has been developed into a valuable biochemical reagent because of its ability to ligate biomolecules together in vitro via a covalent peptide bond. Here we review what is known about the structures and catalytic mechanism of sortase enzymes. Based on their primary sequences, most sortase homologs can be classified into six distinct subfamilies, called class A–F enzymes. Atomic structures reveal unique, class-specific variations that support alternate substrate specificities, while structures of sortase enzymes bound to sorting signal mimics shed light onto the molecular basis of substrate recognition. The results of computational studies are reviewed that provide insight into how key reaction intermediates are stabilized during catalysis, as well as the mechanism and dynamics of substrate recognition. Lastly, the reported in vitro activities of sortases are compared, revealing that the transpeptidation activity of SaSrtA is at least 20-fold faster than other sortases that have thus far been characterized. Together, the results of the structural, computational, and biochemical studies discussed in this review begin to reveal how sortases decorate the microbial surface with proteins and pili, and may facilitate ongoing efforts to discover therapeutically useful small molecule inhibitors.

      PubDate: 2017-06-08T06:29:55Z
      DOI: 10.1016/bs.apcsb.2017.04.008
  • Computational Biochemistry—Enzyme Mechanisms Explored
    • Authors: Martin Culka; Florian Gisdon Matthias Ullmann
      Abstract: Publication date: Available online 27 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Martin Culka, Florian J. Gisdon, G. Matthias Ullmann
      Understanding enzyme mechanisms is a major task to achieve in order to comprehend how living cells work. Recent advances in biomolecular research provide huge amount of data on enzyme kinetics and structure. The analysis of diverse experimental results and their combination into an overall picture is, however, often challenging. Microscopic details of the enzymatic processes are often anticipated based on several hints from macroscopic experimental data. Computational biochemistry aims at creation of a computational model of an enzyme in order to explain microscopic details of the catalytic process and reproduce or predict macroscopic experimental findings. Results of such computations are in part complementary to experimental data and provide an explanation of a biochemical process at the microscopic level. In order to evaluate the mechanism of an enzyme, a structural model is constructed which can be analyzed by several theoretical approaches. Several simulation methods can and should be combined to get a reliable picture of the process of interest. Furthermore, abstract models of biological systems can be constructed combining computational and experimental data. In this review, we discuss structural computational models of enzymatic systems. We first discuss various models to simulate enzyme catalysis. Furthermore, we review various approaches how to characterize the enzyme mechanism both qualitatively and quantitatively using different modeling approaches.

      PubDate: 2017-05-29T05:07:08Z
  • Striking Diversity in Holoenzyme Architecture and Extensive Conformational
           Variability in Biotin-Dependent Carboxylases
    • Authors: Liang Tong
      Abstract: Publication date: Available online 23 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Liang Tong
      Biotin-dependent carboxylases are widely distributed in nature and have central roles in the metabolism of fatty acids, amino acids, carbohydrates, and other compounds. The last decade has seen the accumulation of structural information on most of these large holoenzymes, including the 500-kDa dimeric yeast acetyl-CoA carboxylase, the 750-kDa α6β6 dodecameric bacterial propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and geranyl-CoA carboxylase, the 720-kDa hexameric bacterial long-chain acyl-CoA carboxylase, the 500-kDa tetrameric bacterial single-chain pyruvate carboxylase, the 370-kDa α2β4 bacterial two-subunit pyruvate carboxylase, and the 130-kDa monomeric eukaryotic urea carboxylase. A common theme that has emerged from these studies is the dramatic structural flexibility of these holoenzymes despite their strong overall sequence conservation, evidenced both by the extensive diversity in the architectures of the holoenzymes and by the extensive conformational variability of their domains and subunits. This structural flexibility is crucial for the function and regulation of these enzymes and identifying compounds that can interfere with it represents an attractive approach for developing novel modulators and drugs. The extensive diversity observed in the structures so far and its biochemical and functional implications will be the focus of this review.

      PubDate: 2017-05-24T04:47:30Z
      DOI: 10.1016/bs.apcsb.2017.04.006
  • Computational Glycobiology: Mechanistic Studies of Carbohydrate-Active
           Enzymes and Implication for Inhibitor Design
    • Authors: Andrew P. Montgomery; Kela Xiao; Xingyong Wang; Danielle Skropeta; Haibo Yu
      Abstract: Publication date: Available online 19 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Andrew P. Montgomery, Kela Xiao, Xingyong Wang, Danielle Skropeta, Haibo Yu
      Carbohydrate-active enzymes (CAZymes) are families of essential and structurally related enzymes, which catalyze the creation, modification, and degradation of glycosidic bonds in carbohydrates to maintain essentially all kingdoms of life. CAZymes play a key role in many biological processes underpinning human health and diseases (e.g., cancer, diabetes, Alzheimer's diseases, AIDS) and have thus emerged as important drug targets in the fight against pathogenesis. The realization of the full potential of CAZymes remains a significant challenge, relying on a deeper understanding of the molecular mechanisms of catalysis. Considering numerous unsettled questions in the literature, while with a large amount of structural, kinetic, and mutagenesis data available for CAZymes, there is a pressing need and an abundant opportunity for collaborative computational and experimental investigations with the aim to unlock the secrets of CAZyme catalysis at an atomic level. In this review, we briefly survey key methodology development in computational studies of CAZyme catalysis. This is complemented by selected case studies highlighting mechanistic insights provided by computational glycobiology. Implication for inhibitor design by mimicking the transition state is also illustrated for both glycoside hydrolases and glycosyltransferases. The challenges for such studies will be noted and finally an outlook for future directions will be provided.

      PubDate: 2017-05-24T04:47:30Z
      DOI: 10.1016/bs.apcsb.2017.04.003
  • Collagenolytic Matrix Metalloproteinase Structure–Function
           Relationships: Insights From Molecular Dynamics Studies
    • Authors: Tatyana G. Karabencheva-Christova; Christo Z. Christov; Gregg B. Fields
      Abstract: Publication date: Available online 8 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Tatyana G. Karabencheva-Christova, Christo Z. Christov, Gregg B. Fields
      Several members of the zinc-dependent matrix metalloproteinase (MMP) family catalyze collagen degradation. Experimental data reveal a collaboration between different MMP domains in order to achieve efficient collagenolysis. Molecular dynamics (MD) simulations have been utilized to provide atomistic details of the collagenolytic process. The triple-helical structure of collagen exhibits local regions of flexibility, with modulation of interchain salt bridges and water bridges contributing to accessibility of individual chains by the enzyme. In turn, the hemopexin-like (HPX) domain of the MMP initially binds the triple helix and facilitates the presentation of individual strands to active site in the catalytic (CAT) domain. Extensive positive and negative correlated motions are observed between the CAT and HPX domains when collagen is bound. Ultimately, the MD simulation studies have complemented structural (NMR spectroscopy, X-ray crystallography) and kinetic analyses to provide a more detailed mechanistic view of MMP-catalyzed collagenolysis.

      PubDate: 2017-05-14T01:16:32Z
      DOI: 10.1016/bs.apcsb.2017.04.001
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