Inhibition of SARS-CoV-2 main protease 3CL ^pro by means of α-ketoamide and pyridone-containing pharmaceuticals using in silico molecular docking

Highlights

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  α-ketoamide and pyridone-containing drugs (KPCD) are 3-chymotrypsin-like protease (3CL ^pro) inhibitors.

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  KPCD exhibited significant binding affinity to the catalytic residues of the CL ^pro.

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  The repurposing possibility of six of these approved drugs for COVID-19 treatment.

Abstract

The coronavirus disease infections (COVID-19) caused by a new type of coronavirus (SARS-CoV-2) have been emerging in the entire world. Therefore, it is necessary to find out potential therapeutic pharmaceuticals for this disease. This study investigates the inhibitory effect of the 3-chymotrypsin-like protease of SARS-CoV-2 (3CL ^pro) using pharmaceuticals containing α-ketoamide group and pyridone ring based on molecular docking. Of these, eight pharmaceuticals approved by US-Food and Drug Administration have shown good contact with the catalytic residues of 3CL ^pro. They are telaprevir, temsirolimus, pimecrolimus, aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide. Their binding affinity score ranged from -5.6 to -7.4 kcal/mol. Hydrogen bonds were observed and reported. To the knowledge, this study report for the first time a compound that could be binding to ALA ²⁸⁵, the new residue resulting from genetic modification of 3CL ^pro of SARS-CoV-2 that has increased its catalytic activity 3.6-fold compared with its predecessor 3CL ^pro of SARS-CoV. It is recommended that telaprevir, and pyridone-containing pharmaceuticals including aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide be repurposed for COVID-19 treatment after suitable validation and clinical trials.