Computational guided identification of potential leads from Acacia pennata (L.) Willd. as inhibitors for cellular entry and viral replication of SARS-CoV-2

James H Zothantluanga; Neelutpal Gogoi; Anshul Shakya; Dipak Chetia; H Lalthanzara

doi:10.1186/s43094-021-00348-7

Computational guided identification of potential leads from Acacia pennata (L.) Willd. as inhibitors for cellular entry and viral replication of SARS-CoV-2

Futur J Pharm Sci. 2021;7(1):201. doi: 10.1186/s43094-021-00348-7. Epub 2021 Oct 9.

Authors

James H Zothantluanga¹, Neelutpal Gogoi¹, Anshul Shakya¹, Dipak Chetia¹, H Lalthanzara²

Affiliations

¹ Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam 786004 India.
² Department of Zoology, Pachhunga Univeristy College, Aizawl, Mizoram 796001 India.

Abstract

Background: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in 2019 and is still an on-going pandemic. SARS-CoV-2 uses a human protease called furin to aid in cellular entry and its main protease (M^pro) to achieve viral replication. By targeting these proteins, scientists are trying to identify phytoconstituents of medicinal plants as potential therapeutics for COVID-19. Therefore, our study was aimed to identify promising leads as potential inhibitors of SARS-CoV-2 M^pro and furin using the phytocompounds reported to be isolated from Acacia pennata (L.) Willd.

Results: A total of 29 phytocompounds were reported to be isolated from A. pennata. Molecular docking simulation studies revealed 9 phytocompounds as having the top 5 binding affinities towards SARS-CoV-2 M^pro and furin. Among these phytocompounds, quercetin-3-O-α-L-rhamnopyranoside (C_18), kaempferol 3-O-α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranoside (C_4), and isovitexin (C_5) have the highest drug score. However, C_18 and C_4 were not selected for further studies due to bioavailability issues and low synthetic accessibility. Based on binding affinity, molecular properties, drug-likeness, toxicity parameters, ligand interactions, bioavailability, synthetic accessibility, structure-activity relationship, and comparative analysis of our experimental findings with other studies, C_5 was identified as the most promising phytocompound. C_5 interacted with the active site residues of SARS-CoV-2 M^pro (GLU166, ARG188, GLN189) and furin (ASN295, ARG298, HIS364, THR365). Many phytocompounds that interacted with these amino acid residues were reported by other studies as potential inhibitors of SARS-CoV-2 M^pro and furin. The oxygen atom at position 18, the -OH group at position 19, and the 6-C-glucoside were identified as the pharmacophores in isovitexin (also known as apigenin-6-C-glucoside). Other in-silico studies reported apigenin as a potential inhibitor of SARS-CoV-2 M^pro and apigenin-o-7-glucuronide was reported to show stable conformation during MD simulations with SARS-CoV-2 M^pro.

Conclusion: The present study found isovitexin as the most promising phytocompound to potentially inhibit the cellular entry and viral replication of SARS-CoV-2. We also conclude that compounds having oxygen atom at position 18 (C-ring), -OH group at position 19 (A-ring), and 6-C-glucoside attached to the A-ring at position 3 on a C₆-C₃-C₆ flavonoid scaffold could offer the best alternative to develop new leads against SARS-CoV-2.

Keywords: Apigenin-6-C-glucoside; COVID-19; Furin; Isovitexin; Main protease; Molecular docking; SARS-CoV-2.