Repurposing simeprevir, calpain inhibitor IV and a cathepsin F inhibitor against SARS-CoV-2 and insights into their interactions with M^pro

Abstract

The world has come to a sudden halt due to the incessant spread of a viral pneumonia dubbed COVID-19 caused by the beta-coronavirus, SARS-CoV-2. The main protease of SARS-CoV-2 plays a key role in the replication and propagation of the virus in the host cells. Inhibiting the protease blocks the replication of the virus; therefore it is considered as an attractive therapeutic target. Here we describe the screening of the DrugBank database, a public repository for small molecule therapeutics, to identify approved or experimental phase drugs that can be repurposed against the main protease of SARS-CoV-2. The initial screening was performed on more than 13,000 drug entries in the target database using an energy optimised pharmacophore hypothesis AARRR. A subset of the molecules selected based on the fitness score was further screened using molecular docking by sequentially filtering the molecules through the high throughput virtual screening, extra precision and standard precision docking modalities. The best hits were subjected to binding free energy estimation using the MM-GBSA method. Approved drugs viz, Cobicistat, Larotrectinib and Simeprevir were identified as potential candidates for repurposing. Drugs in the discovery phase identified as inhibitors include the known cysteine protease inhibitors, Calpain inhibitor IV and an experimental cathepsin F inhibitor. In order to analyse the stability of the binding interactions, the known cysteine protease inhibitors viz, Simeprevir, calpain inhibitor IV and the cathepsin F inhibitor in complex M pro were subjected to molecular dynamics simulations at 100 ns. Based on the results Simeprevir was found to be a strong inhibitor of SARS-CoV-2 M pro .

Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning

“…Many drugs among the FDA-approved drugs and also among the natural product datasets bind with high affinity not only to one target protein but also to another one (conivaptan, paritaprevir, simeprevir, dihydroergotamine, ZINC000027215482, ZINC000252515584, loniflavone, procyanidin). There are already published studies reporting the potential of paritaprevir [ 50 ], simeprevir [ 51 ], dihydroergotamine [ 52 ], procyanidin [ 53 ] against SARS-CoV-2. These compounds deserve special attention.…”

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 in Vitro

“…The copyright holder for this this version posted December 2, 2020. ; https://doi.org/10.1101/2020.12.02.408112 doi: bioRxiv preprint binding of different HCV PI to SARS-CoV-2 M pro . [48][49][50][51][52][53][54][55][56][57][58][59][60][62][63][64][65][66][67][68]74 In several of these studies HCV PI were identified as top candidates following screening of large drug libraries, however, some of these studies also yielded contradictory results. Of these studies, 10 identified simeprevir 50,53,58,60,62,63,[65][66][67][68] , 5 paritaprevir 49,53,55,63,66 , 3 glecaprevir [54][55][56] , telaprevir 48,53,64 , boceprevir 48,57,59 and faldaprevir 48,60,…”

Haste makes waste: A critical review of docking‐based virtual screening in drug repurposing for SARS‐CoV‐2 main protease (M‐pro) inhibition

“…An interesting approach used in some of the articles reviewed 48,52,55–57 was to add a pharmacophore‐based procedure before the docking step to enrich the database with some characteristics of the reported M‐pro inhibitors or M‐pro co‐crystallized ligands, or to consider only the compounds that can engage in specific interactions with the M‐pro active site. This strategy makes it possible to identify which of the initial number of compounds are most likely to be inhibitors, even though it requires prior knowledge of the interactions between the receptor and its ligands.…”