Design of inhibitors against severe acute respiratory syndrome (SARS) chymotrypsin‐like protease (3CL^pro) is a potentially important approach to fight against SARS. We have developed several synthetic inhibitors by structure‐based drug design. In this report, we reveal two crystal structures of SARS 3CL^pro complexed with two new inhibitors based on our previous work. These structures combined with six crystal structures complexed with a series of related ligands reported by us are collectively analyzed. To these eight complexes, the structural basis for inhibitor binding was analyzed by the COMBINE method, which is a chemometrical analysis optimized for the protein–ligand complex. The analysis revealed that the first two latent variables gave a cumulative contribution ratio of r² = 0.971. Interestingly, scores using the second latent variables for each complex were strongly correlated with root mean square deviations (RMSDs) of side‐chain heavy atoms of Met⁴⁹ from those of the intact crystal structure of SARS‐3CL^pro (r = 0.77) enlarging the S₂ pocket. The substantial contribution of this side chain (∼10%) for the explanation of pIC₅₀s was dependent on stereochemistry and the chemical structure of the ligand adapted to the S₂ pocket of the protease. Thus, starting from a substrate mimic inhibitor, a design for a central scaffold for a low molecular weight inhibitor was evaluated to develop a further potent inhibitor. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 391–403, 2016.