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Combination of pharmacophore modeling and 3D-QSAR analysis of potential glyoxalase-I inhibitors as anticancer agents |
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| Affiliation: | 1. Department of Sciences, Institute for Information Technologies Kragujevac, University of Kragujevac, Jovana Cvijića bb, Kragujevac 34000, Serbia;2. Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, Kragujevac 34000, Serbia;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade 11000, Serbia;4. Department of Chemistry, Biochemistry and Environmental Protection, University of Novi Sad, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia;5. Institute of Oncology and Radiology of Serbia, Pasterova 14, Belgrade 11000, Serbia;1. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran;2. Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran;3. Behbahan Faculty of Medical Sciences, Behbahan, Iran;4. Salman-e Fars Hospital, Bushehr, Iran;5. Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran |
| Abstract: | Glyoxalase system is an ubiquitous system in human cells which has been examined thoroughly for its role in different diseases. It comprises two enzymes; Glyoxalase I (Glo-I) and Glyoxalase II (Glo-II) which perform detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic bystanders. In silico computer Aided Drug Design approaches were used and ninety two diverse pharmacophore models were generated from eighteen Glyoxalase I crystallographic complexes. Subsequent QSAR modeling followed by ROC evaluation identified a single pharmacophore model which was able to predict the expected Glyoxalase I inhibition. Screening of the National Cancer Institute (NCI) database using the optimal pharmacophore Hypo(3VW9) identified several promising hits. Thirty eight hits were successfully predicted then ordered and evaluated in vitro. Seven hits out of the thirty eight tested compounds showed more than 50% inhibition with low micromolar IC50. |
| Keywords: | Glyoxalase I inhibitors Anticancer agents Pharmacophore modeling Docking ROC analysis |
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