Identification of natural inhibitors against prime targets of SARS-CoV-2 using molecular docking, molecular dynamics simulation and MM-PBSA approaches

Abstract

The recently emerged COVID-19 has been declared a pandemic by the World Health Organization as to date; no therapeutic drug/vaccine is available for the treatment. Due to the lack of time and the urgency to contain the pandemic, computational screening appears to be the best tool to find a therapeutic solution. Accumulated evidence suggests that many phyto-compounds possess anti-viral activity. Therefore, we identified possible phyto-compounds that could be developed and used for COVID-19 treatment. In particular, molecular docking was used to prioritize the possible active phyto-compounds against two key targets namely RNA dependent RNA polymerase (RdRp) and main protease (M^pro) of SARS-CoV-2. In this study, an antiviral drug- Remdesivir (RdRp inhibitor) and Darunavir (M^pro inhibitor) are used as reference drugs. This study revealed that phyto-molecules- Mulberroside-A/C/E/F, Emblicanin A, Nimbolide, and Punigluconin showed high binding affinity against RdRp while Andrographolides, Mulberrosides, Anolignans, Chebulic acid, Mimusopic acid, and Punigluconin showed better binding affinity against M^pro as compared with the reference drug. Furthermore, ADME profiles validated the drug-likeness properties of prioritized phyto-compounds. Besides, to assess the stability, MD simulations studies were performed along with reference inhibitors for M^pro (Darunavir) and RdRp (Remdesivir). Binding free energy calculations (MM-PBSA) revealed the estimated value (ΔG) of M^pro_Darunavir; M^pro_Mulberroside E; RdRp_Remdesivir and RdRp_Emblicanin A were -111.62 ± 6.788, -141.443 ± 9.313, 30.782 ± 5.85 and -89.424 ± 3.130 kJmol^-1, respectively. Taken together, the study revealed the potential of these phyto-compounds as inhibitors of RdRp and M^pro inhibitor that could be further validated against SARS-CoV-2 for clinical benefits.Communicated by Ramaswamy H. Sarma.