title: Structure-based design of P3 moieties in the peptide mimetic factor VIIa inhibitor.
abstract: Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is seen as a promising target for developing new anticoagulant drugs. Structure-based designs of the P3 moiety in the peptide mimetic factor VIIa inhibitor successfully lead to novel inhibitors with selectivity for FVIIa/TF and extrinsic coagulation the same as or even higher than those of previously reported peptide mimetic factor VIIa inhibitors. X-ray crystal structure analysis reveals that one of the novel inhibitors shows improved selectivity by forming interactions between the inhibitor and FVIIa as expected. Another of the novel inhibitors achieves improved selectivity through an unexpected hydrogen bond with Gln217, with a unique bent conformation in FVIIa/TF accompanied by conformational changes of the inhibitor and the protein.
authors.affiliation: Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kadonosuj@chugai-pharm.co.jp <kadonosuj@chugai-pharm.co.jp>
authors.forename: Shojiro
authors.initials: S
authors.lastname: Kadono
authors.forename: Akihisa
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Oh-eda
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yabuta
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Yoshihashi
authors.forename: Takehisa
authors.initials: T
authors.lastname: Kitazawa
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takaki
authors.initials: T
authors.lastname: Koga
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hattori
authors.forename: Takuya
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haramura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kodama
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ono
authors.forename: Toru
authors.initials: T
authors.lastname: Esaki
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Susumu
authors.initials: S
authors.lastname: Itoh
authors.forename: Masateru
authors.initials: M
authors.lastname: Ohta
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kozono
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D015942:Factor VIIa