Multi-conformation representation of Mpro identifies promising candidates for drug repurposing against COVID-19

The COVID-19 main protease (Mpro), one of the conserved proteins of the novel coronavirus is crucial for its replication and so is a very lucrative drug target. Till now, there is no drug molecule that has been convincingly identified as the inhibitor of the function of this protein. The current pandemic situation demands a shortcut to quickly reach to a lead compound or a drug, which may not be the best but might serve as an interim solution at least. Following this notion, the present investigation uses virtual screening to find a molecule which is alraedy approved as a drug for some other disease but could be repurposed to inhibit Mpro. The potential of the present method of work to identify such a molecule, which otherwise would have been missed out, lies in the fact that instead of just using the crystallographically identified conformation of the receptor’s ligand binding pocket, molecular dynamics generated ensemble of conformations has been used. It implicitly included the possibilities of “induced-fit” and/or “population shift” mechanisms of ligand fitting. As a result, the investigation has not only identified antiviral drugs like ribavirin, ritonavir, etc., but it has also captured a wide variety of drugs for various other diseases like amrubicin, cangrelor, desmopressin, diosmin, etc. as the potent possibilities. Some of these ligands are versatile to form stable interactions with various different conformations of the receptor and therefore have been statistically surfaced in the investigation. Overall the investigation offers a wide range of compounds for further testing to confirm their scopes of applications to combat the COVID-19 pandemic. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00894-021-04732-1.