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?

Abstract

The spread of a novel coronavirus SARS-Cov-2 and a resulting COVID19 disease in late 2019 has transformed into a worldwide pandemic and has effectively brought the world to a halt. Proteases 3CL pro and PL pro , responsible for proteolysis of new virions, represent vital inhibition targets for the COVID19 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.

Machine learning prediction of 3CL SARS-CoV-2 docking scores

“…The compounds in our initial S data set have calculated free energies of binding (docking score) ranging from -3.35 kcal/mol to -15.06 kcal/mol with a median score of -8.09 kcal/mol [45] . Compounds from the second L data set, together with the validation set V , achieved docking scores from -1.69 kcal/mol to -15.96 kcal/mol with a median score of -8.97 kcal/mol.…”

“…The 3-dimensional structures of COVID19 related compounds (as previously used in the study of Štekláč et al [45] ) were downloaded from the external PubChem database [67] [October 23, 2020]. After metal complexes (salts) and silicon containing compounds were removed, the first training set contains 866 compounds and is denoted as S (small).…”

“…Nowadays, molecular docking is mainly used for in silico drug design against various SARS-CoV-2 inhibition targets [37] , [38] , [19] , [39] , [40] , [41] , [42] , [43] , [44] . Still, information exchange is not always taken care of, meaning that the complete data is often not accounted for in high-throughput works published with only a few exceptions [22] , [17] , [45] , [43] . In addition, a docking protocol or a molecular dynamics verification takes considerable time and computational demands.…”

“…Herein, two sets of compounds were chosen as the basis of semi-flexible docking into the 3CL pro structure with the PDB code 6WQF. The smaller set S contained 866 compounds [45] (COVID19 related compounds from the external PubChem database [67] ). The larger set L contained 8,696 compounds from the QSAR, docking and molecular dynamics study targeting the inhibition of 3CL pro of Tejera et al [17] .…”

Levocetirizine and montelukast in the COVID-19 treatment paradigm

“…3CL pro plays an essential role in processing polyproteins, the resultant products of which are subsequently utilized in the production of new virions. Additionally, there is a known clinical crossover between ebastine and levocetirizine, the latter considered more potent [27] , [30] , [31] , [32] , [33] , [34] .…”