Antiviral phytocompounds "ellagic acid" and "(+)-sesamin" of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction

Abd Kakhar Umar; James H Zothantluanga; Keerthic Aswin; Saipul Maulana; Muhammad Sulaiman Zubair; H Lalhlenmawia; Mithun Rudrapal; Dipak Chetia

doi:10.1007/s11224-022-01959-3

Antiviral phytocompounds "ellagic acid" and "(+)-sesamin" of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction

Struct Chem. 2022;33(5):1445-1465. doi: 10.1007/s11224-022-01959-3. Epub 2022 May 10.

Authors

Abd Kakhar Umar¹, James H Zothantluanga², Keerthic Aswin³, Saipul Maulana⁴, Muhammad Sulaiman Zubair⁵, H Lalhlenmawia⁶, Mithun Rudrapal⁷, Dipak Chetia²

Affiliations

¹ Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, 45363 Bandung, Indonesia.
² Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, 786004 Assam, India.
³ Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi, 110020 India.
⁴ Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia.
⁵ Department of Pharmacy, Faculty of Math and Natural Sciences, Universitas Tadulako, Palu City, Indonesia.
⁶ Department of Pharmacy, Regional Institute of Paramedical and Nursing Sciences, Aizawl, 796001 Mizoram India.
⁷ Department of Pharmaceutical Chemistry, Rasiklal M. Dhariwal Institute of Pharmaceutical Education & Research, Pune, 411019 Maharashtra India.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected billions and has killed millions to date. Studies are being carried out to find therapeutic molecules that can potentially inhibit the replication of SARS-CoV-2. 3-chymotrypsin-like protease (3CL pro) involved in the polyprotein cleavage process is believed to be the key target for viral replication, and hence is an attractive target for the discovery of antiviral molecules. In the present study, we aimed to identify natural phytocompounds from Bridelia retusa as potential inhibitors of SARS-CoV-2 3CL pro (PDB ID: 6M2N) using in silico techniques. Molecular docking studies conducted with three different tools in triplicates revealed that ellagic acid (BR6) and (+)-sesamin (BR13) has better binding affinity than the co-crystal inhibitor "3WL" of 6M2N. BR6 and BR13 were found to have a high LD₅₀ value with good bioavailability. 3WL, BR6, and BR13 bind to the same active binding site and interacted with the HIS41-CYS145 catalytic dyad including other crucial amino acids. Molecular dynamics simulation studies revealed stability of protein-ligand complexes as evidenced from root-mean-square deviations, root-mean-square fluctuations (RMSF), protein secondary structure elements, ligand-RMSF, protein-ligand contacts, ligand torsions, and ligand properties. BR6 (-22.3064 kcal/mol) and BR13 (-19.1274 kcal/mol) showed a low binding free energy value. The Bayesian statistical model revealed BR6 and BR13 as better protease inhibitors than 3WL. Moreover, BR6 and BR13 had already been reported to elicit antiviral activities. Therefore, we conclude that ellagic acid and (+)-sesamin as natural antiviral phytocompounds with inhibitory potential against SARS-CoV-2 3CL pro.

Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-01959-3.

Keywords: Bridelia retusa; Ellagic acid; Molecular docking; Molecular dynamics; SARS-CoV-2; Sesamin.