Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 M^pro

Novel coronavirus (CoV) is the primary etiological virus responsible for the pandemic that started in Wuhan in 2019-2020. This viral disease is extremely prevalent and has spread around the world. Preventive steps are restricted social contact and isolation of the sick individual to avoid person-to-person transmission. There is currently no cure available for the disease and the search for novel medications or successful therapeutics is intensive, time-consuming, and laborious. An effective approach in managing this pandemic is to develop therapeutically active drugs by repurposing or repositioning existing drugs or active molecules. In this work, we developed a feature-based pharmacophore model using reported compounds that inhibit SARS-CoV-2. This model was validated and used to screen the library of 565 FDA-approved drugs against the viral main protease (M^pro), resulting in 66 drugs interacting with M^pro with higher binding scores in docking experiments than drugs previously reported for the target diseases. The study identified drugs from many important classes, viz. D₂ receptor antagonist, HMG-CoA inhibitors, HIV reverse transcriptase and protease inhibitors, anticancer agents and folate inhibitors, which can potentially interact with and inhibit the SARS-CoV-2 M^pro. This validated approach may help in finding the urgently needed drugs for the SARS-CoV-2 pandemic with infinitesimal chances of failure.