Prediction of Novel Inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through Consensus Docking and Drug Reposition

Abstract

Since the outbreak of the COVID-19 pandemic in December 2019 and its rapid spread worldwide, the scientific community has been under pressure to react and make progress in the development of an effective treatment against the virus responsible for the disease. Here, we implement an original virtual screening (VS) protocol for repositioning approved drugs in order to predict which of them could inhibit the main protease of the virus (M-pro), a key target for antiviral drugs given its essential role in the virus’ replication. Two different libraries of approved drugs were docked against the structure of M-pro using Glide, FRED and AutoDock Vina, and only the equivalent high affinity binding modes predicted simultaneously by the three docking programs were considered to correspond to bioactive poses. In this way, we took advantage of the three sampling algorithms to generate hypothetic binding modes without relying on a single scoring function to rank the results. Seven possible SARS-CoV-2 M-pro inhibitors were predicted using this approach: Perampanel, Carprofen, Celecoxib, Alprazolam, Trovafloxacin, Sarafloxacin and ethyl biscoumacetate. Carprofen and Celecoxib have been selected by the COVID Moonshot initiative for in vitro testing; they show 3.97 and 11.90% M-pro inhibition at 50 µM, respectively.

Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors

“…Currently, scientific community are largely focused in the screening of – (i) FDA-approved drug databases, (ii) clinical trials molecules and/or (iii) previously reported coronavirus inhibitors 9 . In silico virtual screening (VS) techniques are proficient to explore CoV protease inhibitors 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 . Yu and co-workers 40 reported the computational screening and findings with regard to potential binding luteolin and other natural compounds against Mpro.…”

“…Vast amount of in silico VS studies against SARS-CoV-2 Mpro has been reported over past months 26-30, 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 . As the detailed description on the molecular modeling studies is out of Scope for this current communication, readers interested in learning more about recent molecular modeling studies to identify probable CoV protease inhibitors are directed to mentioned references 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72...…”

High-throughput Screening and Experimental Identification of Potent Drugs Targeting SARS-CoV-2 Main Protease

“…Virtual drug screening in silico allows us to rapidly identify possible candidates on a large scale, making drug exploration more effective and economic than traditional strategies 28 . However, the accuracy of prediction obtained with current software could not reach 100%, even when different software programs were combined 29 . Here, we found the exibility of the protein structure, especially the active pocket, has a strong impact on the performance of the docking process.…”

COVID‑19 in China: From epidemiology to treatment (Review)

“…Thus, the Chinese expert group (86,96) recommended the following: i) The advantages and disadvantages of GCS should be fully assessed prior to the prudent use of GCS in critically ill patients with pneumonia; ii) the dosage should be low to medium (≤0.5-1 mg/kg per day methylprednisolone or equivalent) and iii) the duration of treatment should not exceed 7 days. Celecoxib and carprofen are NSAID drugs that were screened by computer-aided analysis, and were demonstrated to potentially exert anti-coronavirus effects (97). However, their exact efficacy requires verification via in vivo and in vitro experiments.…”