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 absenceof a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen outthe effective drug candidates from the approved main protease protein (MPP) inhibitors and theirderivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking wereemployed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors againstHIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamidewere studied as control. The target drug surface hotspot was also investigated through the moleculardocking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likenessof the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and itsanalog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitorcompared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study amongthe 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 hotspotin the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its\u27 analog (CID 131982844),may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on themain protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevirand its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approvedMPP inhibitors. </div

Main protease inhibitors and drug surface hotspots for the treatment of COVID-19: A drug repurposing and molecular docking approach

Here, drug repurposing and molecular docking were employed to screen approved MPP inhibitors and their derivatives to suggest a specific therapeutic agent for the treatment of COVID-19. The approved MPP inhibitors against HIV and HCV were prioritized, while RNA dependent RNA Polymerase (RdRp) inhibitor remdesivir including Favipiravir, alpha-ketoamide were studied as control groups. The target drug surface hotspot was also investigated through the molecular docking technique. Molecular dynamics was performed to determine the binding stability of docked complexes. Absorption, distribution, metabolism, and excretion analysis was conducted to understand the pharmacokinetics and drug-likeness of the screened MPP inhibitors. The results of the 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 inhibitors compared in this study, including remdesivir, Favipiravir, and alpha-ketoamide. A comparative study among the screened putative MPP inhibitors revealed that the amino acids T25, T26, H41, M49, L141, N142, G143, C145, H164, M165, E166, D187, R188, and Q189 are at potentially critical positions for being surface hotspots in the MPP of SARS-CoV-2. The top 5 predicted drugs (Paritaprevir, Glecaprevir, Nelfinavir, and Lopinavir) and the topmost analog showed conformational stability in the active site of the SARS-CoV-2 MP protein. The study also suggested that Paritaprevir and its analog (CID 131982844) might be effective against SARS-CoV-2. The current findings are limited to in silico analysis and lack in vivo efficacy testing; thus, we strongly recommend a quick assessment of Paritaprevir and its analog (CID 131982844) in a clinical trial