Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence
of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out
the effective drug candidates from the approved main protease protein (MPP) inhibitors and their
derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were
employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against
HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide
were studied as control. The target drug surface hotspot was also investigated through the molecular
docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness
of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its
analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor
compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among
the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,
C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot
in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),
may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the
main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir
and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved
MPP inhibitors.