Dr. Serdar DURDAGI
Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul
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withdrawn from the market due to their prolongation of the QT interval.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we focused on several withdrawn drugs from market such as cisapride, terfenadine, astemizole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 An interaction decomposition of withdrawn compounds from market and their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.
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.
- Analitik Kimya
- Anorganik Kimya
- Hesapsal Kimya
- Organik Kimya
- Polimer Kimyasi ve Malzeme Bilimi