Boswellic acid derived molecules as SARS-CoV-2 spike protein inhibitors: A comprehensive virtual screening, triplicate molecular dynamic simulation and biochemical validation.

Background: Coronavirus disease (COVID-19) is a highly infective disease caused by SARS-CoV-2. The SARS-CoV-2 spike protein binds with the human ACE2 receptor to facilitate viral entry into the host cell; therefore, spike protein serves as a potential target for drug development.

Objective: Keeping in view the significance of SARS-CoV-2 spike protein for viral replications, in the current study, we identified the potent inhibitors against SARS-CoV-2 spike protein in order to combat the viral infection.

Methods: In the current study, we screened an in-house library of ~900 natural and synthesized compounds against the spike protein receptor binding domain (RBD) using a structure-based virtual approach, followed by an in-vitro inhibition bioassay.

Results: Seven (C1-C7) potent compounds were identified with docking scores ≥ -6.66 Kcal/mol; their drug-likeness, pharmacokinetic, and pharmacodynamic characteristics were excellent with no toxic effect. Those molecules were subjected to a triplicate simulation for 200 ns, which further confirmed their stable binding with RBD. This tight packing of complexes was reflected by calculated binding free energy, which disclosed higher binding free energy of C4, C7 and C6 than C1-C3, while predicted entropic energy demonstrates higher values for C4, C7 and C1 than the rest of the compounds, indicating more thermodynamic stability in protein due to conformational changes in spike protein induced by binding of C4, C7 and C1. These computational analyses were later validated through in-vitro bioassay. Remarkably, C2-C7 displayed significant inhibitory potential with >76 to 89 % inhibition and C3, C4, C6 and C7 demonstrated the highest inhibition of RBD.

Conclusion: The current findings suggest that compounds C3 and C6 effectively disrupt the function of RBD of SARS-CoV-2 spike protein and can serve as potential drug candidates for spike protein.