Potential Inhibitors of SARS-CoV-2 Main Protease (M^pro) Identified from the Library of FDA Approved Drugs Using Molecular Docking Studies

Abstract

Corona Virus Infectious Disease-2019 (COVID-19) outbreak originated recently at Wuhan, China in December 2019. It has already spread rapidly to more than 200 countries and has been declared a pandemic by WHO. It is caused by a beta-coronavirus named as SARS-CoV-2. There is no definitive cure, either drug or vaccine, to treat or prevent this viral disease. Recently, the crystal structure of the main protease Mpro has been determined. Mpro is responsible for the proteolytic maturation of the polyprotein essential for the viral replication and transcription, which makes it an important drug target. The discovery of new drug molecules may take years before getting to the clinics. So, considering urgency we performed molecular docking studies using FDA approved drugs to identify molecules that could potentially bind to the substrate-binding site and inhibit SARS-CoV-2 main protease (Mpro). We used the Glide module in Schrodinger software suite to perform molecular docking studies followed by MM-GBSA based energy calculations to score the hit molecules. Molecular docking and manual analysis suggest that several drugs may bind and potentially inhibit Mpro. We also performed molecular simulations studies for selected compounds to evaluate protein-drug interactions. Interestingly, we observed only one antiviral compound, Adefovir, in the top50 list of compounds. Considering bioavailability, lesser toxicity, route of administration some of the top-ranked drugs including lumefantrine (antimalarial), dipyridamole (coronary vasodilator), dihydroergotamine (used for treating migraine), hexoprenaline (anti- asthmatic), riboflavin (vitamin B2) and pantethine (vitamin B5) may be taken forward for further in vitro and in vivo experiments to investigate their therapeutic potential.

Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel In Silico Method

“…In another docking study, voriconazole, tobramycin and kanamycin showed potential activity against SARS-CoV-2 M pro [ 33 , 37 ]. Ospemifene was among 51 hits selected in silico against M pro [ 39 ], and propylthiouracil was among the top 20 drugs showing the highest docking score [ 40 ]. Besides, we found oseltamivir, the influenza neuraminidase inhibitor, to have a higher docking score against SARS-CoV-2 M pro than ebselen ( Table 2 ).…”

In-silico drug repurposing for targeting SARS-CoV-2 main protease (Mpro)

“…Recently, several research groups have reported some inhibitors of SARS-CoV-2 main protease (Adem et al, 2020;Khan et al, 2020;Ton et al, 2020;Verma et al, 2020;Zhang et al, 2020). Antiviral drugs and natural compounds are some of the widely explored class of compounds due to their good binding interaction with the main protease.…”

Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel in Silico Method

“…In another docking study, voriconazole, tobramycin and kanamycin showed potential activity against SARS-CoV-2 M pro [33,37]. Ospemifene was among 51 hits selected in silico against M pro [39], and propylthiouracil was among the top 20 drugs showing the highest docking score [40]. Besides, we found oseltamivir, influenza neuraminidase inhibitor to have higher docking score against SARS-CoV-2 M pro than ebselen ( Table 2).…”