Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

Abstract

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

Repurposing Simeprevir, Calpain Inhibitor IV and a Cathepsin F Inhibitor Against SARS-CoV-2: A Study Using in Silico Pharmacophore Modeling and Docking Methods

“…Hence, it is less likely that a drug against SARS-CoV-2 M pro would cross-react with a human protease. Using M pro as the target, our group had recently reported a subset of drugs from the SuperDrug2 database which showed potential to be used against SARS-CoV-2 [16].In the present study, we report the virtual screening of the DrugBank databse, a larger database of drugs using the method of E-pharmacophore modeling and dockingto identify compoundsthat would inhibit M pro and hence could be repurposed against SARS-CoV-2.…”

Facing COVID-19 Via Anti-Inflammatory Mechanism of Action: Molecular Docking and Pharmacokinetic Studies of Six Anti-Inflammatory Compounds Derived from Passiflora edulis

“…In the active research for finding molecule that can treat COVID-19, two approaches are currently being used. One is to identify new uses for FDA-approved drugs (drug repurposing) [5][6], while the other one is to identify from plants biodiversity potential inhibitors or phytochemicals of SARS-CoV-2's main protease using molecular modeling approaches [6][7].…”

Pharmacophore Analyses of SARS-CoV-2 Active Main Protease Inhibitors Using Pharmacophore Query and Docking Study

“…Several studies have demonstrated that αketoamides are effective inhibitors against the main protease [4,5]. Numerous studies have also discovered that some approved drugs may inhibit enzyme activity [6][7][8]. However, the pharmacophore site of the enzyme is still not clear.…”