title: A new type of five-membered heterocyclic inhibitors of basic metallocarboxypeptidases.
abstract: A structure-based virtual screening survey was used to identify potential inhibitors of the human M14 family of metallocarboxypeptidases. A good correlation between docking energy scores and measured K(i) values was observed, indicating an efficient performance of the screening procedure. Among various compounds displaying K(i) values in the low micromolar range, N-(3-chlorophenyl)-4-((5-(3-methoxybenzylthio)-1,3,4-oxadiazol-2-yl)methyl)thiazol-2-amine emerged as the most powerful inhibitor for human carboxypeptidase B (CPB). According to molecular docking, this compound fits into CPB active site cleft through coordination of the catalytic zinc ion with the 1,3,4-oxadiazole moiety. This represents a novel five-membered heterocyclic type of inhibitor for disease-linked metallocarboxypeptidases and an interesting lead for further development.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biociències and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fernández
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Avilés
authors.forename: Josep
authors.initials: J
authors.lastname: Vendrell
mesh_terms: D000818:Animals; D043424:Carboxypeptidase B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D043422:Carboxypeptidases A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007915:Lepidoptera / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D010080:Oxazoles; D043422:Carboxypeptidases A; D043424:Carboxypeptidase B