title: Aromatic organic compounds as scaffolds for metallocarboxypeptidase inhibitor design.
abstract: We have identified and characterized a set of quinoline, naphthalene and quinazoline derivatives as inhibitors of metallocarboxypeptidases, a class of metal-dependent proteolytic enzymes. The aromatic organic compounds were selected from a high-throughput screening survey and, with some exceptions, showed a good correlation between inhibitory potency and docking energy value. The in vitro inhibition tests gave K(i) values in the lower micromolar range for metallocarboxypeptidases with different specificities, and a tendency to behave as more powerful inhibitors of CPB was observed for most of the compounds tested. The kinetic results were further analyzed by structural analysis via molecular docking. The most potent aromatic organic inhibitor docks to human CPB mostly through burial of its hydrophobic moiety deep into the enzyme's active site cleft and by interacting with the catalytic zinc ion. The significance of our results in designing inhibitors against disease-related CPs from the identified ligands is examined herein.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, E-08193 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; D001665:Binding Sites; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015195:Drug Design; D006801:Humans; D008667:Metalloproteins / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry*; D009930:Organic Chemicals / Q000737:chemistry; D011487:Protein Conformation; D011799:Quinazolines / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D008667:Metalloproteins; D009281:Naphthalenes; D009930:Organic Chemicals; D011799:Quinazolines; D011804:Quinolines; D011994:Recombinant Proteins; D002268:Carboxypeptidases