Biyoinformatik ve Genetik Bölümü Koleksiyonu

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    Article
    Citation Count: 14
    Exploration of the binding pocket of histone deacetylases: the design of potent and isoform-selective inhibitors
    (Tübitak, 2017) Yelekçi, Kemal; Yelekçi, Kemal
    Histone deacetylases (HDACs) are enzymes that act on histone proteins to remove the acetyl group and thereby regulate the chromatin state. HDACs act not only on histone protein but also nonhistone proteins that are key players in cellular processes such as the cell cycle, signal transduction, apoptosis, and more. “Classical” HDACs have been shown to be promising targets for anticancer drug design and development. However, the selectivity of HDAC inhibitors for HDAC isoforms remains the motivation of current research in this field. Here, we explored Class I HDACs and HDAC6 by sequence alignment and structural superimposition, catalytic channel extraction, and identification of critical residues involved in HDAC catalysis. Based on the general pharmacophore features of known HDAC inhibitors, we developed a library of compounds by scaffold hopping on a fragment hit identified via structurebased virtual screening of the molecular fragment library retrieved from the Otava database. Molecular docking assay revealed five of these compounds to have increased potency and selectivity for HDACs 1 and 2. Furthermore, their predicted absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties were consistent with those of drug-like compounds. With further modelingbased and experimental investigations, we believe that these findings may offer additional potential HDAC inhibitors with improved selectivity
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    Citation Count: 2
    Intrinsic Dynamics and Causality in Correlated Motions Unraveled in Two Distinct Inactive States of Human beta(2)-Adrenergic Receptor
    (Amer Chemical Soc, 2019) Söğünmez, Nuray; Akten, Ebru Demet
    The alternative inactive state of the human beta(2)-adrenergic receptor originally exposed in molecular dynamics simulations was investigated using various analysis tools to evaluate causality between correlated residue-pair fluctuations and suggest allosteric communication pathways. A major conformational shift observed in the third intracellular loop (ICL3) displayed a novel inactive state featuring an inaccessible G protein binding site blocked by ICL3 and an expanded orthosteric ligand binding site. Residue-based mean square fluctuation and stiffness calculations revealed a significant mobility decrease in ICL3 which induced a mobility increase in the remaining loop regions. This indicates conformational entropy loss in one mobile region being compensated by residual intermolecular motions in other mobile regions. Moreover the extent motions decreased and correlations that once existed between transmembrane helices shifted toward regions with increased mobility. Conditional time-delayed cross-correlation analysis identified distinct driver follower relationship profiles. Prior to its packing freely moving ICL3 was markedly driven by transmembrane helix-8 whereas once packed ICL3 controlled future fluctuations of nearby helices. Moreover two transmembrane helices (H5 and H6) started to control future fluctuations of a remote site the extracellular loop ECL2. This clearly suggests that allosteric coupling between extra- and intracellular parts intensified in agreement with the receptor's well recognized feature which is the inverse proportionality between activity and the degree of coupling.