Computational screening of molecular fragments and fragment linking to design novel inhibitors for SARS-Cov-2 main protease
Publicly available fragment libraries should be screened against the binding pocket of SARS-Cov-2 target Main protease (MPro) to identify fragments which bind to various regions of the binding pockets with a reasonably good affinity. The binding pocket, where the co-crystal native ligand binds, should be considered for screening fragments. A dataset of known active fragments retrieved from PDB from the PanDDA analysis should be used to validate the binding interactions made by the screened fragments. The screened high-affinity fragments of adjacent sub-pockets of the binding site of the target need to be linked to generate new molecules. These newly generated molecules should be subjected to blind docking to prioritize molecules with stable interactions with key binding site residues. The obtained molecules should be filtered using ADMET filters and the selected compound-target complexes should be subjected to molecular dynamics simulations (for 20-50 ns) to verify the stabilities of the complexes. Binding pattern of the known inhibitors should be used as the reference for validating the binding affinities and interactions of the newly designed molecules. The top screened de novo molecules should be submitted.