title: Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza-decaline scaffold.
abstract: 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 r(2)  = 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 Met(49) 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 pIC50 s 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.
authors.affiliation: Department of Neurochemistry, Tohoku University Graduate School of Medicine, Aoba-Ku Sendai, 980-8575, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Teruya
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto, 607-8412, Japan.
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto, 607-8412, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimamoto
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto, 607-8412, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: R&D Center, Protein Wave Co, Nara, 631-0006, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sanjoh
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Eiki
authors.initials: E
authors.lastname: Yamashita
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto, 607-8412, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Akaji
mesh_terms: D000086782:Coronavirus 3C Proteases; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry; D057786:Peptidomimetics / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D057786:Peptidomimetics; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases
keywords: COMBINE analysis for inhibitor design, hydrophobic interaction; SARS 3CL protease; aza-decaline; aza-decaline scaffold; crystal structure complexed with inhibitor; inhibitor