Identification of potent COVID-19 main protease inhibitors by loading of favipiravir on Mg12O12 and Zn12O12 nanoclusters: an in silico strategy for COVID-19 treatment

Abstract

Pandemic new severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has increased throughout the world. There is no effective treatment against this virus until now. Since its appearance in Wuhan, China in December 2019, SARS-CoV-2 becomes the largest challenge the world is opposite today, including the discovery of an antiviral drug for this virus. Several viral proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them the papain-like protease (PLpro) and the main protease (Mpro). Inhibition of these proteases would target viral replication, viral maturation and suppression of host innate immune responses. Potential candidates have been identified to show inhibitory effects against Mpro, both in biochemical assays and viral replication in cells. There are different molecules such as lopinavir and favipiravir considerably inhibit the activity of Mpro in vitro. Different studies have shown that structurally improved favipiravir and other similar compounds can inhibit SARS-CoV-2 main protease. In this work, we study the interactions between favipiravir with Mg₁₂O₁₂ and Zn₁₂O₁₂ nanoclusters by density functional theory (DFT) and quantum mechanics atoms in molecules (QMAIM) methods to summarize the ability to load favipiravir onto Mg₁₂O₁₂ and Zn₁₂O₁₂ nanoclusters. Favipiravir-Mg₁₂O₁₂ and favipiravir-Zn₁₂O₁₂ lowest structures complexes were chosen to dock inside the SARS-CoV-2 main protease by molecular docking study. The molecular docking analysis revealed that the binding affinity of Mg₁₂O₁₂ and Zn₁₂O₁₂ nanoclusters inside the Mpro receptor is larger than that of favipiravir. Also, the loading of favipiravir on the surface of Mg₁₂O₁₂ and Zn₁₂O₁₂ nanoclusters increased the binding affinity against the Mpro receptor. Subsequently, 100 ns molecular dynamics simulation of the favipiravir-Mg₁₂O₁₂, and favipiravir-Zn₁₂O₁₂ docked inside the Mpro complexes established that favipiravir-Mg₁₂O₁₂, forms the most stable complex with the Mpro. Further molecular mechanics Poisson Boltzmann surface area (MMPBSA) analyses using the MD trajectories also demonstrated the higher binding affinity of favipiravir-Mg₁₂O₁₂ inside the Mpro. In summary, this study demonstrates a new way to characterize leads for novel anti-viral drugs against SARS-CoV-2, by improving the drug ability of favipiravir via loading it on Mg₁₂O₁₂ and Zn₁₂O₁₂ nanoclusters.Communicated by Ramaswamy H. Sarma.

Keywords: DFT; Mg12O12; QMAIM; SARS-CoV-2 main protease; Zn12O12; favipiravir; molecular docking; molecular dynamics simulation.