25 (S)-Hydroxycholesterol acts as a possible dual enzymatic inhibitor of SARS-CoV-2 Mpro and RdRp-: an insight from molecular docking and dynamics simulation approaches

The coronavirus disease (COVID-19) pandemic has rapidly extended globally and killed approximately 5.83 million people all over the world. But, to date, no effective therapeutic against the disease has been developed. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enters the host cell through the spike glycoprotein (S protein) of the virus. Subsequently, RNA-dependent RNA polymerase (RdRp) and main protease (M-pro) of the virus mediate viral transcription and replication. Mechanistically inhibition of these proteins can hinder the transcription as well as replication of the virus. Recently oxysterols and its derivative, such as 25 (S)-hydroxycholesterol (25-HC) has shown antiviral activity against SARS-CoV-2. But the exact mechanisms and their impact on RdRp and M-pro have not been explored yet. Therefore, the study aimed to identify the inhibitory activity of 25-HC against the viral enzymes RdRp and M-pro simultaneously. Initially, a molecular docking simulation was carried out to evaluate the binding activity of the compound against the two proteins. The pharmacokinetics (PK) and toxicity parameters were analyzed to observe the 'drug-likeness' properties of the compound. Additionally, molecular dynamics (MD) simulation was performed to confirm the binding stability of the compound to the targeted protein. Furthermore, molecular mechanics generalized Born surface area (MM-GBSA) was used to predict the binding free energies of the compound to the targeted protein. Molecular docking simulation identified low glide energy -51.0 kcal/mol and -35.0 kcal/mol score against the RdRp and M-pro,M- respectively, where MD simulation found good binding stability of the compound to the targeted proteins. In addition, the MM/GBSA approach identified a good value of binding free energies (Delta G bind) of the compound to the targeted proteins. Therefore, the study concludes that the compound 25-HC could be developed as a treatment and/or prevention option for SARS-CoV-2 disease-related complications. Although, experimental validation is suggested for further evaluation of the work. Communicated by Ramaswamy H. Sarma

Automated summary

The COVID-19 pandemic has caused a global crisis with millions of deaths, and effective treatment options are still lacking. This study explores the potential antiviral activity of 25-HC, an oxysterol derivative, against SARS-CoV-2. Through molecular docking, molecular dynamics simulation, and MM/GBSA analysis, the study demonstrates the inhibitory activity and binding stability of 25-HC against viral enzymes RdRp and M-pro. These findings suggest the potential of 25-HC as a treatment and prevention option for COVID-19 complications.