title: Discovery of potent thermolysin inhibitors using structure based virtual screening and binding assays.
abstract: In the present work, 22 compounds of the U.S. NCI compound library (size 273K) were identified as putative thermolysin binders by structure based virtual screening with the ICM software (ICM-VLS). In vitro competitive binding assays confirmed that 12 were thermolysin binders. Thermolysin binding modes of the 12 compounds were studied by docking using ICM and Molegro Virtual Docker (MVD). The most potent inhibitor had an IC(50) value of 6.4 x 10(-8) mM (NSC250686, 1 beta-D-arabinofuranosyl-N(4)-lauroylcytosine). The structure of this compound is quite different from the other 11 compounds. Nine out of the 12 compounds contained a similar chemical skeleton (3-nitrobenzamide derivatives) and have IC(50) values ranging from 697.48 to 0.047 mM. The ICM-VLS score and the activity profiles (pIC(50) values) were compared and found to be somewhat linearly correlated (R(2) = 0.78). Kinetic studies showed that, except for NSC285166 (oxyquinoline), the compounds are competitive thermolysin inhibitors.
authors.affiliation: Department of Pharmacology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, N-9037, Tromsø, Norway.
authors.forename: Mahmud Tareq Hassan
authors.initials: MT
authors.lastname: Khan
authors.forename: Ole-Martin
authors.initials: OM
authors.lastname: Fuskevåg
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
mesh_terms: D000465:Algorithms; D001407:Bacillus / Q000201:enzymology; D001667:Binding, Competitive; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D054547:National Cancer Institute (U.S.); D011480:Protease Inhibitors / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D012984:Software; D013820:Thermolysin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D014481:United States
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D013820:Thermolysin