论文

Since the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several variants have caused a persistent pandemic. Consequently, it is crucial to develop new potential anti-SARS-CoV-2 drugs with specificity. To minimize potential failures and preserve valuable clinical resources for the development of other useful drugs, researchers must enhance their understanding of the interactions between drugs and SARS-CoV-2. While numerous crystal structures of the SARS-CoV-2 main protease (SCM) and its inhibitors have been reported, they provide only static snapshots and fail to capture the dynamic nature of SCM/inhibitor interactions. Herein, we conducted molecular dynamics simulations for five SCM complexes: ritonavir (SCM/RTV), lopinavir (SCM/LPV), the identified inhibitor N3 (SCM/N3), the approved inhibitor ensitrelvir (SCM/ESV), and the approved drug nirmatrelvir (SCM/NMV). Additionally, we explored the potential for covalent bond formation in the N3 and NMV inhibitors through QM/MM calculations using Umbrella sampling. The results show that the binding site is highly flexible to fit those five different inhibitors and each compound has its unique binding mode at the same binding site. Moreover, the binding affinities of positive and negative inhibitors to SCM exhibit significant differences. By gaining insights into the dynamics, we can potentially elucidate why lopinavir/ritonavir, initially considered promising, failed to effectively treat COVID-19. Furthermore, understanding the mechanistic aspects of N3 and NMV inhibition on SCM not only contributes to rational drug discovery against COVID-19 but also aids future studies on the catalytic mechanisms of main proteases in other novel coronaviruses.