An in-silico evaluation of COVID-19 main protease with clinically approved drugs

Abstract

A novel strain of coronavirus, namely, SARS-CoV-2 identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor, we performed blind docking studies on the main virus protease M ^pro with eight approved drugs belonging to four pharmacological classes such as: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. When docked against M ^pro crystal structure, these two compounds revealed a minimum binding energy of -8.87 and -8.71 kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Further, to study the interaction mechanism and conformational dynamics of protein-ligand complexes, Molecular dynamic simulation and MM/PBSA binding free calculations were performed. Our results showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein. Moreover, the ADMET analysis also indicated drug-likeness properties. Thus it is suggested that the identified compounds can inhibit Chymotrypsin-like protease (3CL ^pro) of SARS-CoV-2.

Graphical abstract

Highlights

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  Lymecycline and Mizolastine fit into M ^pro binding substrate pocket with a binding energies of -8.87 kcal/mol and -8.71 kcal/mol, respectively.

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  Lymecycline and Mizolastine had 168 and 256 binding modes detected in the binding substrate pocket, respectively.

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  ADMET analysis indicated drug-likeness properties of both Lymecycline and Mizolastine.

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  Molecular dynamic simulation and MM/PBSA binding free calculations showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein