Computational studies evidenced the potential of steroidal lactone to disrupt surface interaction of SARS-CoV-2 spike protein and hACE2.

The critical event in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis is recognition of host cells by the virus, which is facilitated by protein-protein interaction (PPI) of viral Spike-Receptor Binding Domain (S-RBD) and Human Angiotensin Converting Enzyme 2-Receptor (hACE2-R). Thus, disrupting the interaction between S-RBD and hACE2-R is widely accepted as a primary strategy for managing COVID-19. The purpose of this study is to assess the ability of three steroidal lactones (SL) (4-Dehydrowithaferin A, Withaferin A, and Withalongolide A) derived from plants to disrupt the PPI of S-RBD and hACE2-R under two conditions (CON-I and CON-II) using in-silico methods. Under CON-I, 4-Dehydrowithaferin A destabilizing the interactions between S-RBD and hACE2-R, as indicated by an increase in binding energy (BE) from -1028.5 kJ/mol (control) to -896.12 kJ/mol 4-Dehydrowithaferin A exhibited a strong interaction with S-RBD GLY496 with a hydrogen bond occupancy (HBO) of 37.33%. Under CON-II, Withalongolide A was capable of disrupting all types of PPI, as evidenced by an increased BE from -913 kJ/mol (control) to -133.69 kJ/mol and an increased distance (>3.55 nm) between selected AAR combinations of S-RBD and hACE2-R. Withalongolide A formed a hydrogen bond with TYR453 (97%, HBO) of S-RBD, which is required for interaction with hACE2-R's HIS34. Our studies demonstrated that SL molecules have the potential to disrupt the S-RBD and hACE2-R interaction, thereby preventing SARS-CoV-2 from recognizing host cells. The SL molecules can be considered for additional in-vitro and in-vivo studies with this research evidence.

Exploring structurally diverse plant secondary metabolites as a potential source of drug targeting different molecular mechanisms of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pathogenesis: An in silico approach (preprint)

Plants are endowed with a large pool of structurally diverse small molecules known as secondary metabolites. Present study aims to virtually screen these plant secondary metabolites (PMS) for their possible anti-SARS-CoV-2 properties targeting four protein/enzymes which determines viral pathogenesis. Results of molecular docking and data analysis revealed a unique pattern of structurally similar PSM interacting with the target protein. Among the top-ranked PSM with lower binding energy, >50% were triterpenoids against viral spike protein, >32% were flavonoids and their glycoside against Human transmembrane serine protease, >16% were flavonol glycosides and >16% were Anthocyanidine against viral main protease and >13% were flavonol glycoside against viral RNA dependet RNA polymerase. The primary concern about these PSM is their bioavailability. However, several PSM recorded higher bioavailability score and found fulfilling drug-likeness characters as per Lipinski's rule. Natural occurrence, biotransformation, bioavailability of selected PSM and their interaction with the target site of selected proteins were discussed in detail. Further, we hypothesized the use of selected PSM to cure the COVID-19 by inhibiting the process of viral host cell recognition and replication in host cell. However, these PSM needs thorough in vitro and in vivo evaluation before taking them to clinical trials.