title: Structure based optimization of chromen-based TNF-α converting enzyme (TACE) inhibitors on S1' pocket and their quantitative structure-activity relationship (QSAR) study.
abstract: A series of coumarin based TACE inhibitors were designed to bind in S1' pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1' pocket and the TACE inhibitory activity well.
authors.affiliation: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Jee Sun
authors.initials: JS
authors.lastname: Yang
authors.forename: Kwangwoo
authors.initials: K
authors.lastname: Chun
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Misun
authors.initials: M
authors.lastname: Cho
authors.forename: Jeongjea
authors.initials: J
authors.lastname: Seo
authors.forename: Doona
authors.initials: D
authors.lastname: Song
authors.forename: Hongchul
authors.initials: H
authors.lastname: Yoon
authors.forename: Chun-Ho
authors.initials: CH
authors.lastname: Park
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Joe
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Choi
authors.forename: Myung-Hwa
authors.initials: MH
authors.lastname: Kim
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D001578:Benzopyrans; D001665:Binding Sites; D003374:Coumarins; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D055672:Static Electricity
chemical_list: D001578:Benzopyrans; D003374:Coumarins; D004791:Enzyme Inhibitors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat