No abstract

Rhinovirus infections are estimated to be 70% of virus-related cold and flu-like illnesses. The disastrous impact of human rhinovirus infections costs healthcare systems billions annually. Herein, an in-house target-bound pharmacophore-based virtual screening protocol, outlined in our previous publications, was employed in identifying potential drug lead of 3C protease, based on the structural characteristics of rupintrivir. The two novel hits HRV-ZINC01537619 and HRV-ZINC601135028 may be commissioners of the new group of 3C proteases inhibitors against human rhinoviruses. Interestingly, both ZINC01537619 and ZINC601135028 interact with catalytic residues His40 and Cys147, respectively. This is a significant phenomenon which gives hope that viral replication inhibition is possible. These promising compounds now pave a fundamental new route toward the successful inhibition of the virus.

In light of the rapid rise of an influenza pandemic, the constant genetic mutations of H5N1 influenza viruses pose a threat. Mutations at the sialic site are often responsible for multiple drug resistance. To design effective new inhibitors, it is necessary to undertake research into the mechanism of resistance of influenza viruses and their rapid mutations. The molecular dynamic simulation technique has been an instrumental tool in understanding how proteins function from an atomic perspective. A thorough investigation has not been conducted using molecular dynamics to examine the impact of these mutations (I222K, H274Y, and H274Y-I222K) on Peramivir. This study investigates the effects of I222K, H274Y, H274Y-I222K substitution on the neuraminidase–Peramivir complex and identifies responsible residues for complex conformations. The mutations caused distorted Peramivir orientation in the enzyme active site, which affected the inhibitor’s binding. In the presence of various mutations, interaction between protein and ligand became less thermodynamically favorable. We observed the following trend in binding free energy difference: WT<I222<H274Y<H274Y-I222K. As a result of the thermodynamic instability of the mutant complexes, Peramivir’s potency is reduced due to impaired binding interactions. Wild type complex displays thermodynamic stability and strong protein-ligand interactions due to their high total energy contributions and low residue flexibility. Based on the energy decomposition analysis, Arg117, Arg224, and Arg292 contributed the largest residual energy for the binding of Peramivir to wild type and mutants. These residues are thought to play a key role in the formation of the binding pocket between Peramivir and neuraminidase. This study provides a basis for investigating the effects of other mutations on Peramivir’s efficacy against the H5N1 virus.