Investigation of ritonavir analogs antiretroviral natural compounds against SARS-CoV-2 envelope protein

Abstract

Since the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, there has been a surge in scientific research to find a permanent cure for the disease. The main challenge in effective drug discovery is the continuously mutating nature of the SARS-CoV-2 virus. Thus, we have used the I-TASSER modeling to predict the structure of the SARS-CoV-2 viral envelope protein followed by combinatorial computational assessment to predict its putative potential small molecule inhibitors. As early treatment with ritonavir in combination was associated with faster time to clinical improvement and/or virological clearance, we aimed to retrieve analogs of ritonavir to find ideal inhibitors for SARS-CoV-2 viral envelope protein. The collected ligands were screened against the predicted binding pocket of viral envelope protein using extra precision (XP) docking protocol and the first four best-docked compounds were studied for complex stability using 300 ns all-atom molecular dynamics simulations embedding within the cellular membrane. Among the selected compounds, ZINC64859171 and ZINC1221429 showed considerable stability and interactions by comparison to the reference compound, i.e., Ritonavir (ZINC3944422). Moreover, the post-simulation analysis suggested the considerable binding affinity and induced conformation changes in the respective docked complexes against Ritonavir. Altogether, the obtained results demonstrated the putative potential of screened ritonavir analogs, i.e., ZINC64859171, against the envelope protein of SARS-CoV-2 and can be considered for further drug development in the treatment of the COVID-19 pandemic. Communicated by Ramaswamy H. Sarma