Evaluation of potential flavonoid inhibitors of glyoxalase-I based on virtual screening and in vitro studies. Issue 5 (3rd May 2016)

• Record Type: Journal Article
• Authors: Yadav, Aarti; Kumar, Rajnish; Sunkaria, Aditya; Singhal, Nitin; Kumar, Manoj; Sandhir, Rajat
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 34:Issue 5(2016)
• Page Start: 993
• Page End: 1007
• Publication Date: 2016-05-03
• Subjects: cancer -- docking -- glyoxalase-I -- methylglyoxal -- naringin -- QM/MM; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2015.1064830
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract : Glyoxalase-I (GLO-I) is a component of the ubiquitous detoxification system involved in the conversion of methylglyoxal (MG) tod -lactate in the glycolytic pathway. MG toxicity arises from its ability to form advanced glycation end products. GLO-I has been reported to be frequently overexpressed in various types of cancer cells. In this study, we performed structure-based virtual screening of focused flavonoids commercial library to identify potential and specific inhibitors of GLO-I. The compounds were ranked based on Glide extra precision docking score and five hits (curcumin, quercetin, morin, naringin and silibinin) were selected on the basis of their interaction with active site amino acid residues of GLO-I. Mixed mode QM/MM calculation was performed on the top-scoring hit to ascertain the role of zinc ion in ligand binding. In addition, the identified hits were subjected to MM/GBSA binding energy prediction, ADME prediction and similarity studies. The hits were tested in vitro for cell viability, and GLO-I inhibition. Naringin (ST072162) was found to be most potent inhibitor of GLO-I among the identified hits with highest glide XP dock score of −14.906. These findings suggest that naringin could be a new scaffold for designing inhibitors against GLO-I with potential application as anticancer agents.