Computational investigation on natural quinazoline alkaloids as potential inhibitors of the main protease (Mpro) of SARS_CoV_2

Drug discovery is still behind in the race compared to vaccine discovery in fighting COVID-19. Recently, a few alkaloids from a traditional Indian medicinal plant, Vasaka (Justicia adhatoda), have been linked computationally to the main protease (Mpro) of SARS_CoV_2. To expand the knowledge and for further investigation, we have selected 41 quinazoline alkaloids from two natural product databases to create an adequate library and performed detailed computational studies against the main protease (Mpro) of SARS_CoV_2. The screening of the library was carried out through blending the rigid docking and pharmacokinetic analysis that resulted in nine alkaloids as initial leads against Mpro. These nine alkaloids were further subjected to advance flexible docking using first reference famotidine for the analysis of structure-based interactions. For further selection, a second screening was carried out based on binding energies and interaction profiles that yielded three alkaloids namely CNP0416047, 3-hydroxy anisotine and anisotine as hits. The stereo-electronic features of hit alkaloids were further investigated through additional structure-based E-pharmacophore mapping against a second reference, known X77 ligand. Additionally, the reactivity of hit alkaloids at the binding site of the protein was estimated by measuring the electron distribution on the frontier molecular orbitals and HOMO-LUMO band energies. Finally, the stabilities of complexes between hit alkaloids with the protein were accessed extensively using robust molecular dynamics simulation through RMSD, RMSF, Rg, and MM-PBSA calculation. Thus, this study identifies three natural quinazoline alkaloids as potential inhibitors of MPro through extensive computational analysis.