Discovery of Potent Thermolysin Inhibitors Using Structure Based Virtual Screening and Binding Assays

• Published in: Journal of medicinal chemistry Vol. 52; no. 1; pp. 48 - 61
• Main Authors: Khan, Mahmud Tareq Hassan, Fuskevåg, Ole-Martin, Sylte, Ingebrigt
• Format: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 08.01.2009
• Subjects: Algorithms; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacillus - enzymology; Binding, Competitive; Biological and medical sciences; Computational Biology - methods; Computer Simulation; Drug Evaluation, Preclinical - methods; Inhibitory Concentration 50; Kinetics; Ligands; Medical sciences; Models, Molecular; Molecular Conformation; National Cancer Institute (U.S.); Pharmacology. Drug treatments; Protease Inhibitors - analysis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Protein Binding; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Software; Thermolysin - antagonists & inhibitors; Thermolysin - chemistry; Thermolysin - metabolism; United States; United States; Enzyme; Virtual screening; Enzyme inhibitor; Metalloendopeptidases; Molecular interaction; Inhibitor enzyme complex; Thermolysin; In vitro; Modeling; Peptidases; Biological fixation; Structure activity relation; Molecular model; Hydrolases; Antibacterial agent; Pyrimidine nucleoside
• DOI: 10.1021/jm8008019
• ISSN: 0022-2623

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 IC50 value of 6.4 × 10−8 mM (NSC250686, 1β-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 IC50 values ranging from 697.48 to 0.047 mM. The ICM-VLS score and the activity profiles (pIC50 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.