Computational Screening of Newly Designed Compounds against Coxsackievirus A16 and Enterovirus A71

Outbreaks of hand, foot, and mouth disease (HFMD) that occur worldwide are mainly caused by the Coxsackievirus-A16 (CV-A16) and Enterovirus-A71 (EV-A71). Unfortunately, neither an anti-HFMD drug nor a vaccine is currently available. Rupintrivir in phase II clinical trial candidate for rhinovirus showed highly potent antiviral activities against enteroviruses as an inhibitor for 3C protease (3Cpro). In the present study, we focused on designing 50 novel rupintrivir analogs against CV-A16 and EV-A71 3Cpro using computational tools. From their predicted binding affinities, the five compounds with functional group modifications at P1 ', P2, P3, and P4 sites, namely P1 '-1, P2-m3, P3-4, P4-5, and P4-19, could bind with both CV-A16 and EV-A71 3Cpro better than rupintrivir. Subsequently, these five analogs were studied by 500 ns molecular dynamics simulations. Among them, P2-m3, the derivative with meta-aminomethyl-benzyl group at the P2 site, showed the greatest potential to interact with the 3Cpro target by delivering the highest number of intermolecular hydrogen bonds and contact atoms. It formed the hydrogen bonds with L127 and K130 residues at the P2 site stronger than rupintrivir, supported by significantly lower MM/PB(GB)SA binding free energies. Elucidation of designed rupintrivir analogs in our study provides the basis for developing compounds that can be candidate compounds for further HFMD treatment.

Automated summary

Outbreaks of hand, foot, and mouth disease (HFMD) caused by Coxsackievirus-A16 (CV-A16) and Enterovirus-A71 (EV-A71) have led to a need for effective treatments. In this study, 50 novel rupintrivir analogs were designed against CV-A16 and EV-A71 using computational tools. Five compounds, namely P1'-1, P2-m3, P3-4, P4-5, and P4-19, showed better binding affinity with 3C protease (3Cpro) of both CV-A16 and EV-A71 compared to rupintrivir. Molecular dynamics simulations revealed that P2-m3 displayed the greatest potential for interaction with the 3Cpro target, forming stronger hydrogen bonds with specific residues and showing lower binding free energies. These designed rupintrivir analogs provide a basis for the development of candidate compounds for HFMD treatment.