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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 C 6 –C 3 –C 6  flavonoid scaffold could offer the best alternative to develop new leads against SARS-CoV-2.

future journal of pharmaceutical sciences

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