Binding kinetics study of SARS-CoV-2 main protease and potential inhibitors via molecular dynamics simulations

The pandemic COVID-19 was induced by the novel coronavirus SARS-CoV-2. The virus main protease (M-pro) cleaves the coronavirus polyprotein translated from the viral RNA in the host cells. Because of its crucial role in virus replication, M-pro is a potential drug target for COVID-19 treatment. Herein, we study the interactions between M-pro and three HIV-1 protease (HIV-1 PR) inhibitors, Lopinavir (LPV), Saquinavir (SQV), Ritonavir (RIT), and an inhibitor PF-07321332, by conventional and replica exchange molecular dynamics (MD) simulations. The association/dissociation rates and the affinities of the inhibitors were estimated. The three HIV-1 PR inhibitors exhibit low affinities, while PF-07321332 has the highest affinity among these four simulated inhibitors. Based on cluster analysis, the HIV-1 PR inhibitors bind to M-pro at multiple sites, while PF-07321332 specifically binds to the catalytically activated site of M-pro. The stable and specific binding is because PF-07321332 forms multiple H-bonds to His163 and Glu166 simultaneously. The simulations suggested PF-07321332 could serve as an effective inhibitor with high affinity and shed light on the strategy of drug design and drug repositioning.

Automated summary

The main protease (M-pro) of the novel coronavirus SARS-CoV-2 plays a crucial role in virus replication and is a potential drug target for COVID-19 treatment. In this study, the interactions between M-pro and three HIV-1 protease inhibitors (Lopinavir, Saquinavir, Ritonavir) and an inhibitor PF-07321332 were studied using molecular dynamics simulations. The results showed that PF-07321332 had the highest affinity among the four simulated inhibitors and specifically bound to the catalytically activated site of M-pro. The simulations suggested that PF-07321332 could serve as an effective inhibitor with high affinity and provide insights into drug design and repositioning strategies.