ABSTRACT: Several existing drugs have gained initial consideration due to their therapeutic characteristics against COVID-19 (Corona Virus Disease 2019). Hydroxychloroquine (HCQ) was proposed as possible therapy for shortening the duration of COVID-19, but soon after this, it was discarded. Similarly, known antiviral compounds were also proposed and investigated to treat COVID-19. We report a pharmacophore screening using essential chemical groups derived from HCQ and known antivirals to search a natural compound chemical space. Molecular docking of HCQ under physiological condition with spike protein, 3C-like protease (3CLpro), and RNA-dependent RNA polymerase (RdRp) of SARS-CoV2 showed - 8.52 kcal/mole binding score with RdRp, while the other two proteins showed relatively weaker binding affinity. Docked complex of RdRp-HCQ is further examined using 100 ns molecular dynamic simulation. Docking and simulation study confirmed active chemical moieties of HCQ, treated as 6-point pharmacophore to screen ZINC natural compound database. Pharmacophore screening resulted in the identification of potent hit molecule [(3S,3aR,6R,6aS)-3-(5-phenylsulfanyltetrazol-1-yl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]N-naphthalen-ylcarbamate from natural compound library. Additionally, a set of antiviral compounds with similar chemical scaffolds are also used to design a separate ligand-based pharmacophore screening. Antiviral pharmacophore screening produced a potent hit 4-[(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)-(2-hydroxyphenyl)methyl]-1,5-dimethyl-2-phenylpyrazol-3-one containing essential moieties that showed affinity towards RdRp. Further, both these screened compounds are docked (- 8.69 and - 8.86 kcal/mol) and simulated with RdRp protein for 100 ns in explicit solvent medium. They bind at the active site of RdRp and form direct/indirect interaction with ASP618, ASP760, and ASP761 catalytic residues of the protein. Successively, their molecular mechanics Poisson Boltzmann surface area (MMPBSA) binding energies are calculated over the simulation trajectory to determine the dynamic atomistic interaction details. Overall, this study proposes two key natural chemical moieties: (a) tetrazol and (b) phenylpyrazol that can be investigated as a potential chemical group to design inhibitors against SARS-CoV2 RdRp.
