Identification of potential COVID-19 main protease inhibitors using structure-based pharmacophore approach, molecular docking and repurposing studies

Acta Pharmaceutica

Dahabiyeh Lina A.¹  Alabed Shada J.¹  Daoud Safa² 

[1] Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan;Department of Pharmaceutical, Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science, Private University, Amman, Jordan;

关键词: covid-19;    main protease;    pharmacophore;    structure-based modeling;    docking study;    remdesivir;    repurposing;   

DOI  :  10.2478/acph-2021-0016

来源: DOAJ

【 摘 要 】

The current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today’s diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.

【 授权许可】

Unknown