In Silico Studies of Crystal Structure of HCV NS5B Polymerase and Inhibitor Complex

Quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics simulations were performed to study the hydrogen bonding and polar interactions of an inhibitor namely 2-{[(5-bromothiophen-2-yl) sulfonyl] amino}- 4-chlorobenzoic acid with HCV NS5B polymerase. Using the initial poses, our aim is to identify the minimum energy positions and calculate binding affinities of inhibitor to HCV. Results suggest that the accuracy of binding affinity prediction can be significantly affected by the proper treatment of the hydrogen bonding and polar interactions. Using this protocol, we successfully identified important poses of low RMSD with respect to crystallographic structure from the initially docked poses. This work shows that the most important energetic component contributing to binding for this particular protein-ligand system is the conformational energy. In addition, formation of hydrogen bonds can produce favorable van der Waals interactions with some important residues. This systematic study can provide guidance for the choice of QM/MM MD methods and design of new inhibitors targeting HCV. (c) 2018 Elsevier Ltd. All rights reserved.