The main protease (M pro ) of SARS_CoV_2 virus is involved in the processing of non-structured polyproteins and essential for viral replication within the host cell (1, 2, 3). The published crystal structure of M pro (PDB ID 6LU7) has paved the road for the structure-based design of inhibitors ( ) and we analyzed the crystal structure with the same purpose. The M pro crystallized as a homodimer of two protomers, where each protomer consists of 306 amino acid residues and divided into three domains: Domain I (amino acids 8 -101), Domain II (amino acids 102 -184) and Domain III (amino acids 201 -303) (Figure ). Additionally, each Domain II and III are connected by a Loop (amino acids 185 -200) that is crucial for the enzymatic action of main proteases . The substrate-binding site and catalytic dyad (Cys145, His41) is located at a cleft between Domain I and Domain II. Furthermore, the substrate binding site is divided into four sub-sites: S1 located nearby Cys145, S1' located nearby His41, S2 located nearby hydrophobic residues namely Tyr54, and S4 located nearby the Loop region. Moreover, we have selected famotidine as one of the reference compounds as it's linked to M Pro inhibition computationally and also implicated to SARS_CoV_2 growth inhibition . Additionally, we have chosen X77 molecule as a second reference in E-pharmacophore modeling as X77 is a non-covalent inhibitor and the co-crystal structure of X77-M Pro is available (PDB ID 6W63) .