• Apr
    11
    2014

    Name: Assoc. Prof. Serdar DURDAĞI

    Affiliation: Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul

    Location: Chemistry Seminar Room

    Hour: 14:00

    The human ether-a-go-go related gene 1 (hERG1), which codes for a potassium ion channel, is a
    key element in the cardiac delayed rectified potassium current, IKr, and plays an important role in
    the normal repolarization of the heart’s action potential. [1-6] Many approved drugs have been
    withdrawn from the market due to their prolongation of the QT interval. Most of these drugs have
    high potencies for their principal targets and are often irreplaceable, thus “rehabilitation” studies
    for decreasing their high hERG1 blocking affinities, while keeping them active at the binding
    sites of their targets, have been proposed to enable these drugs to re-enter the market. In our lab,
    we focused on several withdrawn drugs from market such as cisapride, terfenadine, astemizole
    due to their high hERG1 blocking affinities. We tested a priori strategy to predict cardiotoxicity
    risks of compounds using De Novo drug design approach with combination of homology
    modeling, protein engineering, molecular docking and Molecular Dynamics simulations to
    generate a strategy for the rehabilitation of these drugs. We focused on two key receptors, a target
    interaction with the principle receptors of these molecules and an off-target interaction with
    hERG1 channels. An analysis of the fragment interactions of these compounds at their principal
    target receptors and hERG1 central cavities (using Subbotina/Durdagi Model) helped us to
    identify the key chemical groups responsible for the drug activity and hERG1 blockade. A set of
    novel derivatives with reduced cardiotoxicity was then proposed using an in-silico two-tier
    approach. An interaction decomposition of withdrawn compounds from market and their
    derivatives allowed us for the identification of key active scaffolds and functional groups that are
    responsible for the unwanted blockade of hERG1.

    References:

    1. Durdagi, S.; Guo, J.; Lees-Miller, J.; Duff, H.J.; Noskov, S.Y. (2012) “Structure-Guided
    Topographic Mapping and Mutagenesis to Elucidate Binding sites for the hERG1 Potassium
    Channel (KCNH2) Activator-NS1643” J. Pharmacol. Exp. Therap. 342, 441-452.
    2. Durdagi, S.; Deshpande, S.; Duff, H. J.; Noskov, S.Y. (2012) “Modeling of Open, Closed, and
    Open-Inactivated States of the hERG1 Channel: Structural Mechanisms of the State-Dependent
    Drug Binding” J. Chem. Inf. Model. (ACS) 10, 2760-2774.
    3. Durdagi, S; Duff, HJ; Noskov, S.Y. (2011) “Combined Receptor and Ligand-Based Approach to
    the Universal Pharmacophore Model Development for Studies of Drug Blockade to the hERG1
    Pore Domain” J. Chem. Inf. Model. (ACS) 51, 463-474,
    4. Subbotina, J.; Yarov-Yarovoy, V.; Lees-Miller, J.; Durdagi, S.; Guo, J.Q.; Duff, H.J.; Noskov,
    S.Y. (2011) “Structural Refinement of the hERG1 Pore and Voltage-Sensing Domains with
    ROSETTA-Membrane and Molecular Dynamics Simulations” Proteins, 78, 2922-2934.
    5. Durdagi, S.; Randall, T.; Duff, H.J.; Chamberlin, A.; Noskov, S.Y. (2014) “Rehabilitating druginduced
    long-QT promoters: In-silico design of hERG-neutral cisapride analogues with retained
    pharmacological activity” BMC Pharmacol Toxicol. 15:14, 1-15.
    6. Durdagi, S.; Subbotina, J.; Lees-Miller, J.; Guo, J.; Duff, H.J.; Noskov, S.Y. (2010) “Insights into
    the Molecular Mechanism of hERG1 Channel Activation and Blockade by Drugs”, Curr. Med.
    Chem. 17, 3514-3532.