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  Subjects -> MEDICAL SCIENCES (Total: 7706 journals)
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Showing 1 - 200 of 3562 Journals sorted alphabetically
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African Health Sciences     Open Access   (Followers: 2)
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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)
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ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3)
American Journal of Biomedical Engineering     Open Access   (Followers: 11)
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)
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American Journal on Addictions     Hybrid Journal   (Followers: 8)
American medical news     Free   (Followers: 3)
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Amyloid: The Journal of Protein Folding Disorders     Hybrid Journal   (Followers: 5)
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Anales de la Facultad de Medicina, Universidad de la República, Uruguay     Open Access  
Anales del Sistema Sanitario de Navarra     Open Access   (Followers: 1)
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Anthropological Review     Open Access   (Followers: 23)
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Anwer Khan Modern Medical College Journal     Open Access   (Followers: 2)
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Applied Medical Informatics     Open Access   (Followers: 10)
Arab Journal of Nephrology and Transplantation     Open Access   (Followers: 1)
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Arquivos de Ciências da Saúde     Open Access  
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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: 12)
Arterial Hypertension     Open Access   (Followers: 1)
Artificial Intelligence in Medicine     Hybrid Journal   (Followers: 13)
Artificial Organs     Hybrid Journal   (Followers: 1)
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Asia Pacific Family Medicine     Open Access   (Followers: 1)
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Asia Pacific Journal of Clinical Trials : Nervous System Diseases     Open Access  
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Biomedicine     Open Access   (Followers: 2)
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)
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Asian Journal of Transfusion Science     Open Access   (Followers: 1)
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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: 9)
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Avicenna     Open Access   (Followers: 3)
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Bangladesh Journal of Anatomy     Open Access   (Followers: 1)
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Journal Cover
Advances in Protein Chemistry and Structural Biology
Journal Prestige (SJR): 0.791
Citation Impact (citeScore): 2
Number of Followers: 20  
 
  Full-text available via subscription Subscription journal
ISSN (Online) 1876-1623
Published by Elsevier Homepage  [3159 journals]
  • Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic
           Reaction Mechanisms
    • Abstract: Publication date: Available online 13 August 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Jon Ainsley, Alessio Lodola, Adrian J. Mulholland, Christo Z. Christov, Tatyana G. Karabencheva-Christova The combined quantum mechanics/molecular mechanics (QM/MM) methods have become a valuable tool in computational biochemistry and received versatile applications for studying the reaction mechanisms of enzymes. The approach combines the calculations of the electronic structure of the active site by QM, with modeling of the protein environment using MM force field, which allows the long-range electrostatics and steric effects on the enzyme reactivity to be accounted for. In this review, we review some key theoretical and computational aspects of the method and we also present some applications to particular enzymatic reactions such as tryptophan-7-halogenase, cyclooxygenase-1, and the epidermal growth factor receptor.
       
  • Computational Methods for Efficient Sampling of Protein Landscapes and
           Disclosing Allosteric Regions
    • Abstract: Publication date: Available online 25 July 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Canan Atilgan Methods developed toward computational exploration of protein landscapes have become standardized tools to assess biophysical experimental findings. They are also used on their own right to discover the workings of the protein as a molecular machine, potential sites of interest for protein functioning, allosteric regions in proteins, and communication pathways between different sites on a protein. With the development of reliable force fields that describe interactions in biomolecules, molecular dynamics (MD) simulations have become the prime tool for this purpose. While it is now straightforward to carry out MD simulations up to microseconds with current computers readily available to researchers, many processes of biological interest occur on several of orders of magnitudes slower timescales. Thus, the latter problems are attackable through MD by a handful of researchers that have access to the most powerful computers. Alternatively, physics-based methods to interrogate the protein energy landscape are in continuous development to circumvent this problem. In addition to opening the routes for advancement to a large number of researchers that have access to modest computational resources, they have the advantage of providing an understanding of the mechanisms that govern protein dynamics. Here we discuss network-based approaches geared toward understanding protein dynamics. These include (i) construction of residue networks which view proteins as networks of nodes connected through local interactions and (ii) construction of proteins as elastic networks whose modes of motion may be manipulated to achieve allowed conformational changes. Limitations of the methods as well as opportunities for future exploitation are described.
       
  • The OECD Principles for (Q)SAR Models in the Context of Knowledge
           Discovery in Databases (KDD)
    • Abstract: Publication date: Available online 4 May 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(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.
       
  • Computational Methods to Discover Compounds for the Treatment of Chagas
           Disease
    • Abstract: Publication date: Available online 16 March 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(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.
       
  • Computational Methods for Epigenetic Drug Discovery: A Focus on Activity
           Landscape Modeling
    • Abstract: Publication date: Available online 5 March 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(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.
       
  • Chapter Eight - Protein and Peptides for Elderly Health
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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.
       
  • Chapter Seven - In Silico Tools and Databases for Designing Peptide-Based
           Vaccine and Drugs
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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.
       
  • Chapter Six - Smart Cell-Penetrating Peptide-Based Techniques for
           Intracellular Delivery of Therapeutic Macromolecules
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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.
       
  • Chapter Five - Chimeric Small Antibody Fragments as Strategy to Deliver
           Therapeutic Payloads
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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.
       
  • Chapter Four - Transglutaminase and Sialyltransferase Enzymatic Approaches
           for Polymer Conjugation to Proteins
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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.
       
  • Chapter Three - Dynamical Behavior of Somatostatin-14 and Its Cyclic
           Analogues as Analyzed in Bulk and on Plasmonic Silver Nanoparticles
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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.
       
  • Chapter Two - Therapeutic Monoclonal Antibodies Delivery for the
           Glioblastoma Treatment
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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.
       
  • Chapter Ten - The Structure/Function Relationship in Antimicrobial
           Peptides: What Can we Obtain From Structural Data'
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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.
       
  • Chapter Eight - Investigating the Influence of Hotspot Mutations in
           Protein–Protein Interaction of IDH1 Homodimer Protein: A Computational
           Approach
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 111Author(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 positions 132 and 178 were found to be pathogenic and neutral respectively. 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.
       
  • Chapter Seven - Defining Pharmacological Targets by Analysis of
           Virus–Host Protein Interactions
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 111Author(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.
       
  • Chapter Six - Development of Protein–Protein Interaction Inhibitors for
           the Treatment of Infectious Diseases
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 111Author(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.
       
  • Chapter Five - Subcellular Targeting of Nitric Oxide Synthases Mediated by
           Their N-Terminal Motifs
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 111Author(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.
       
  • Chapter Four - Multifaceted Nucleolin Protein and Its Molecular Partners
           in Oncogenesis
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 111Author(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.
       
  • Chapter Three - Targeting the Architecture of Deregulated Protein
           Complexes in Cancer
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 111Author(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.
       
  • Chapter Two - Targeting Intramembrane Protein–Protein Interactions:
           Novel Therapeutic Strategy of Millions Years Old
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 111Author(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.
       
  • Chapter One - Homo- and Heterodimerization of Proteins in Cell Signaling:
           Inhibition and Drug Design
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 111Author(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.
       
  • Chapter Eleven - Linear Analogues of the Lipopeptide Battacin With Potent
           In Vitro Activity Against S. aureus
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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 = 200 nmol) against S. aureus. Furthermore, this lipopeptide was resilient toward degradation conditions when exposed to rat serum proteases for up to 8 h.
       
  • Chapter Nine - Peptide Derivatives of Erythropoietin in the Treatment of
           Neuroinflammation and Neurodegeneration
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 112Author(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.
       
  • Chapter Nine - Human Interactomics: Comparative Analysis of Different
           Protein Interaction Resources and Construction of a Cancer Protein–Drug
           Bipartite Network
    • Abstract: Publication date: 2018Source: Advances in Protein Chemistry and Structural Biology, Volume 111Author(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.
       
 
 
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