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Start date: 2010End date: 2019Subject: search.filters.subject.HumanType: search.filters.itemtype.Book Chapter

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    Application of multiscale simulation tools on GPCRs. An example with angiotensin II type 1 receptor
    (Humana Press Inc. humana@humanapr.com, 2018) Erol, Ismail; Aksoydan, Busecan; Kantarcioglu, Isik; Durdagi, Serdar; Erol, Ismail, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Kantarcioglu, Isik, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey
    G protein-coupled receptors (GPCRs) represent the biggest class of membrane proteins included in signal transduction cascade across the biological lipid bilayers. They are essential target structures for cell signaling and are of great commercial interest to the pharmaceutical industry (~50% of marketed drugs and ~25% of top-selling drugs targeting this receptor family). Recent advances made in molecular biology and computational chemistry open new avenues for the design of new therapeutic compounds. Molecular biology has recently provided the crystal structures of a few ligand-bound GPCRs in active and inactive states, which can be used as accurate templates in modeling studies. Computational chemistry offers a range of simulation, multiscale modeling with ligand- and structure-based approaches, and virtual screening tools for definition and analysis of protein-ligand, protein-protein, and protein-DNA interactions. Development of new approaches and algorithms on statistical methods and free energy simulations help to predict novel optimal compounds. Integrated approach to drug discovery that combines quantum mechanics calculations, molecular docking, molecular dynamics (MD) simulations, quantitative structure-activity relationships (QSAR), and de novo design studies under a single umbrella can be used for decreasing the risk of false-positive results. Each method has its own pros and cons and, when used alone, is not likely to yield very useful results. However, when these methods are combined with positive feedback loops, they may enhance each other and successful drug leads may be obtained. Moreover, investigating the activation mechanisms and atomistic determinants of ligand binding to GPCR targets would allow greater safety in the human life. © 2019 Elsevier B.V., All rights reserved.
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    Effects of cholesterol on GPCR function: Insights from computational and experimental studies
    (Springer New York LLC barbara.b.bertram@gsk.com, 2019) Kiriakidi, Sofia; Kolocouris, Antonios D.; Liapakis, George; Ikram, Saima; Durdagi, Serdar; Mavromoustakos, Thomas M.; Kiriakidi, Sofia, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece; Kolocouris, Antonios D., Department of Pharmacy, National & Kapodistrian University of Athens, School of Health Sciences, Athens, Greece; Liapakis, George, Department of Pharmacology, University of Crete Medical School, Heraklion, Greece; Ikram, Saima, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Mavromoustakos, Thomas M., Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
    The extensive experimental and computational evidences revealed that cholesterol is involved in the drug binding to G protein-coupled receptor (GPCR) targets that is influenced by the membrane environment and external functions. These multifunctional factors make the understanding of the molecular mechanism of action in greater detail an entirely difficult task. Significant efforts have been made for better understanding the role of multi-directional specific, receptor-dependent interactions of cholesterol, and its effects on drug design and development. Additional efforts must be made in this complex system in order to shed more light on cholesterol molecular basis of action. The results of molecular simulations that complemented experimental data may reveal new aspects of GPCR-cholesterol interactions and may provide a comprehensive understanding of receptor function. © 2019 Elsevier B.V., All rights reserved.