Molecular modeling on 3C protease/inhibitor complexes involving hand foot mouth disease

Abstract

Hand, foot and mouth disease (HFMD) outbreaks frequently occur with children during the rainy season even becoming epidemic in some case. In general, HFMD patients have mild symptoms, that clear quickly. The enterovirus A71 (EV-A71) is a variant of the virus that causes severe pathogenic HFMD and may lead to death. In 2012, over 100000 HFMD cases were reported in Vietnam with 166 deaths due to EV-71 infection. HFMD occurrs in many countries e.g. Malaysia, China, Singapore, Vietnam, Brunei, Cambodia, and Great Britain. No vaccine or drug against HFMD is available. Rupintrivir, a broad-spectrum inhibitor, is a drug candidate for HFMD treatment, Another candidate is SG85, which is reported to have a better binding affinity than rupintrivir against CV-A16. Both inhibitors exhibit a comparable affinity against EV-A71 3C protease (3Cpro). In this work, the molecular information in term of the binding of the two inhibitors to the proteases will be elucidated. We aimed to investigate the inhibitory mechanisms of some potent compounds (e.g. rupintrivir) against the 3Cpro of the virus CV-A16, EV-A71 and EV-D68 in order to understand their biological activity and to develop procedures to improve their inhibitory potency. Molecular Docking and Molecular Dynamics simulation (MD simulation) are used as computational tools. The second part of this study is search for other potent HFMD inhibitors this was performed by screening several compound libraries (ZINC database, DrugBank and ChemBL) against the CV-A16 and EV-A71 3C proteases using steered molecular dynamic (SMD) simulations. Based on the hypothesis that a higher force is needed for pulling a more effective ligand from the protein target, the two analogs of rupintrivir containing the hydroxyl methyl at -meta and -para positions of the P2 side chain required an averaged rupture force higher than rupintrivir and SG85. The obtained information could be useful for the further development of anti-HFMD drugs.