2.5. Generation of pharmacophore hypothesis (model)

An energy-optimized pharmacophore (e-pharmacophore) model combines the advantages of structure-based and ligand-based drug-design theories, and can be used to rapidly screen ligands based on pharmacophore properties (Salam et al., 2009; Negi et al., 2014). Using the ‘Develop Pharmacophore hypothesis’ option in Maestro v12.2 tasks view mode, pharmacophore sites were generated from the receptor with redocked co-crystalized ligand (M^pro-X77) complex, preserving a maximum of seven pharmacophore features as default. Pharmacophore chemical properties include: hydrogen-bond acceptor (A), represented as vectors, hydrogen-bond donor (D) as projected points, aromatic ring (R) as ring, positive ionizable (P), and negative ionizable (N) (Veeramachaneni et al., 2015). Explicit matching was required in the e-pharmacophore approach for generation of the most energetically favorable site. The hypothesis settings were configured to treat atoms as projected points with a radii scaling factor of 0.50 and limit excluded volume shell to 5.0 Å.