Structural investigation of vesnarinone at the pore domains of open and open-inactivated states of hERG1 K+ channel

In this study, the dynamics of vesnarinone bounded hERG1 K+ channels are investigated using in silico approaches such as molecular docking, molecular dynamics (MD) simulations, MM/PBSA (Molecular Mechanics/Poisson Boltzmann Surface Area) calculations and Principal Component Analysis (PCA). Vesnarinone (a cardiotonic agent) falls into a category of drugs that inhibit phosphodiesterase 3-type (PDE3) enzymes. PDE3 enzymes have specific roles in the dehydyrolysis of intracellular second messengers 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP). Thus, PDE3 inhibitors elevate the intracellular concentrations of these substrates. However, it is also known that vesnarinone inhibits the human ether-a-go-go-related gene (hERG) channels. Since inhibition of hERG channels may cause life-threatening arrhythmias, leading to Torsades de pointes (TdP) and long QT syndrome (LQTS), it is important to understand the particular residue-drug interactions and hERG channel dynamics. Applying the computational approaches in this study, have helped to elucidate the possible binding patterns and time evaluation dynamics of this drug at hERG1 channel models (both in its open and open-inactivated states) together with the crucial amino acid residues that mostly contribute in binding processes via interaction binding energy decomposition analysis. (c) 2017 Elsevier Inc. All rights reserved.