J Mol Struct . "Identification of Nafamostat and VR23 as COVID-19 drug candidates by targeting 3CL pro and PL pro."

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J Mol Struct


. 2021 Feb 15;130094.
doi: 10.1016/j.molstruc.2021.130094. Online ahead of print.
"Identification of Nafamostat and VR23 as COVID-19 drug candidates by targeting 3CL ^pro and PL ^pro."


Deep Bhowmik ¹ , Ravi Datta Sharma ² , Amresh Prakash ³ , Diwakar Kumar ¹



Affiliations

• PMID: 33612858
• PMCID: PMC7884051
• DOI: 10.1016/j.molstruc.2021.130094

Abstract

The sudden increase in the COVID-19 epidemic affected by novel coronavirus 2019 has jeopardized public health worldwide. Hence the necessities of a drug or therapeutic agent that heal SARS-CoV-2 infections are essential requirements. The viral genome encodes a large Polyprotein, further processed by the main protease/ 3C-like protease (3CL^pro) and papain-like proteases (PL^pro) into 16 nonstructural proteins to form a viral replication complex. These essential functions of 3CL^pro and PL^pro in virus duplication make these proteases a promising target for discovering potential therapeutic candidates and possible treatment for SARS-CoV-2 infection. This study aimed to screen a unique set of protease inhibitors library against 3CL^pro and PL^pro of the SARS-CoV-2. A molecular docking study was performed using PyRx to reveal the binding affinity of the selected ligands and molecular dynamic simulations were executed to assess the three-dimensional stability of protein-ligand complexes. The pharmacodynamics parameters of the inhibitors were predicted using admetSAR. The top two ligands (Nafamostat and VR23) based on docking scores were selected for further studies. Selected ligands showed excellent pharmacokinetic properties with proper absorption, bioavailability and minimal toxicity. Due to the emerging and efficiency of remdesivir and dexamethasone in healing COVID-19 patients, ADMET properties of the selected ligands were thus compared with it. MD Simulation studies up to 100ns revealed the ligands' stability at the target proteins' binding site residues. Therefore, Nafamostat and VR23 may provide potential treatment options against SARS-CoV-2 infections by potentially inhibiting virus duplication though more research is warranted.

Keywords: 3CLpro; ADMET; Docking; Drug; PLpro; SARS-CoV-2; and Simulation.