3CLpro and PLpro affinity, a docking study to fight COVID19 based on 900 compounds from PubChem and literature. Are there new drugs to be found?

The spread of a novel coronavirus SARS-CoV-2 and a resulting COVID-19 disease in late 2019 has transformed into a worldwide pandemic and has effectively brought the world to a halt. Proteases 3CL(pro) and PLpro, responsible for proteolysis of new virions, represent vital inhibition targets for the COVID-19 treatment. Herein, we report an in silico docking study of more than 860 COVID19-related compounds from the PubChem database. Molecular dynamic simulations were carried out to validate the conformation stability of compound-ligand complexes with best docking scores. The MM-PBSA approach was employed to calculate binding free energies. The comparison with ca. 50 previously reported potential SARS-CoV-2's proteases inhibitors show a number of new compounds with excellent binding affinities. Anti-inflammatory drugs Montelukast, Ebastine and Solumedrol, the anti-migraine drug Vazegepant or the anti-MRSA pro-drug TAK-599, among many others, all show remarkable affinities to 3CL(pro) and with known side effects present candidates for immediate clinical trials. This study reports thorough docking scores summary of COVID19-related compounds found in the PubChem database and illustrates the asset of computational screening methods in search for possible drug-like candidates. Several yet-untested compounds show affinities on par with reported inhibitors and warrant further attention. Furthermore, the submitted work provides readers with ADME data, ZINC and PubChem IDs, as well as docking scores of all studied compounds for further comparisons. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The global pandemic of COVID-19 caused by the novel coronavirus has led to the exploration of potential inhibitors for key proteases like 3CL(pro) and PLpro. In this study, computational docking analysis of over 860 COVID19-related compounds revealed new molecules with excellent binding affinities, including known drugs such as Montelukast and Solumedrol, which could be candidates for immediate clinical trials. Thorough docking scores summary and computational screening methods have shown promising results in the search for drug-like candidates.