The Discovery of inhibitors of the SARS-CoV-2 S protein through computational drug repurposing

Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation

“…Compared with our group's previous projects, in which the same main procedure was applied [18,20,21], similar results were obtained. The methodology, again, was sufficient to produce at least one experimentally active compound to inhibit the SARS-CoV-2 M pro main protease.…”

“…As also demonstrated in our previous studies [18,20,21], the docking protocol employed in the current study, exploring the DCM database, yielded at least one experimentally active compound among those selected as candidate inhibitors of the SARS-CoV-2 M pro protease. Departing from the smooth energetic profile found for the active compound (Figure S1), a further binding analysis was performed.…”

“…To analyze the time evolution of the free binding energy, Δ G binding, of all the initially selected compounds, the MMGBSA approach was employed. Following the previous procedures established by us [ 18 , 20 , 21 ], an iterative process, consisting of the extension of the simulation length of the previous molecular dynamics simulations, was performed for the analysis. During each iteration, complexes that exhibited a smooth Δ G binding fluctuating behavior during the last 20 ns of the cMD simulation were kept to continue with the protocol.…”

“…Moreover, computational chemistry studies are a cost-effective strategy, as has been shown in many recently published studies. A few of them have focused on the virtual screening of FDA-approved compounds with the successful identification of drugs presenting inhibitory activity regarding coronavirus in vitro [ 18 , 19 ]. Natural products have also been considered as promising starting points in the discovery process of antiviral agents, including those identified by virtual screening and subsequent experimental in vitro validation for their inhibitory profile in regard to the SARS-CoV-2 M pro [ 20 , 21 , 22 , 23 , 24 ].…”

“…Accordingly, in the present study, we report the results of a virtual screening study of the DCM database aimed at identifying prospective inhibitors of the SARS-CoV-2 M pro main protease. For this purpose, we employed a robust protocol previously developed in our group that shows reasonable success rates [ 18 , 20 , 21 ]. Specifically, two distinct and independent protocols of ensemble molecular docking were applied to identify inhibitors from the DCM database targeting different representative structures of the enzyme.…”