Discovery of Multi-Target-Directed Ligands against SARS-CoV-2 through Targeting the Structurally Conserved Main Protease

The ongoing COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the Coronaviridae family. The disease has infected more than 1 million individuals worldwide with a mortality rate ranging from 5 to 10 %. It has also imposed extreme challenges on global health, economy, and social behavior. Due to the unavailability of therapeutics, several efforts are going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (MPro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of MPro, we have performed phylogenetic and SSN analysis, that depicted divergence of Coronaviridae MPro in five clusters specific to viral hosts. This clustering was also corroborated with the structural comparison of MPro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. This conservation can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 MPro. In agreement with this, we performed screening of the custom-made library of ~ 7000 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 MPro as the primary target. It has been observed that natural molecules like d-Viniferin, Myricitrin, Taiwanhomoflavone A, Lactucopicrin 15-oxalate, Nympholide A, Biorobin, Phyllaemblicin B and other several molecules show strong binding with the SARS-CoV-2 MPro. Most of the predicted lead molecules are from Vitis vinifera, also reported for anti-tussive and/or antiviral activities. These molecules also showed strong binding with other main targets RdRp and hACE-2. We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection.