title: Crystal structure of a complex of human chymase with its benzimidazole derived inhibitor.
abstract: The crystal structure of human chymase complexed with a novel benzimidazole inhibitor, TJK002, was determined at 2.8 Å resolution. The X-ray crystallographic study shows that the benzimidazole inhibitor forms a non-covalent interaction with the catalytic domain of human chymase. The hydrophobic fragment of the inhibitor occupies the S1 pocket. The carboxylic acid group of the inhibitor forms hydrogen bonds with the imidazole N(ℇ) atom of His57 and/or the O(γ) atom of Ser195 which are members of the catalytic triad. This imidazole ring of His57 induces π-π stacking to the benzene ring of the benzimidazole scaffold as P2 moiety. Fragment molecular orbital calculation of the atomic coordinates by X-ray crystallography shows that this imidazole ring of His57 could be protonated with the carboxyl group of Asp102 or hydroxyl group of Ser195 and the stacking interaction is stabilized. A new drug design strategy is proposed where the stacking to the protonated imidazole of the drug target protein with the benzimidazole scaffold inhibitor causes unpredicted potent inhibitory activity for some enzymes.
authors.affiliation: Teijin Institute for Bio-medical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Kakuda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Koizumi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mizuno
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Muroga
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawamura
authors.forename: Midori
authors.initials: M
authors.lastname: Takimoto-Kamimura
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry*; D053818:Chymases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D011487:Protein Conformation
chemical_list: D001562:Benzimidazoles; D053818:Chymases
keywords: FMO calculation; benzimidazole; chymase inhibitor; crystal structure