2.5. E-pharmacophore modeling: E-pharmacophore model was built using the recently published cocrystal structure of X77 inhibitor with protein M Pro (PDB ID 6W63). For this purpose, the co-crystal structure was retrieved from RCSB database, then 'interactive pharmacophore model' was generated in BIOVIA Discovery studio by selecting the protein as receptor and the X77 inhibitor as ligand. The protocol was set to calculate maximum ten pharmacophores with maximum features 6 at minimum inter-feature distance 2 with steric volume excluded for all types of non-bond interactions. The vacant E-pharmacophore was then mapped with the energy-optimized structures of selected alkaloids based on the common features. Prior to mapping, alkaloids were structurally optimized using CHARMM force field with Momary-Rone partial charge at pH 7.4 and all possible tautomers, stereoisomers and protonation states were generated.