title: Evaluation of potential flavonoid inhibitors of glyoxalase-I based on virtual screening and in vitro studies.
abstract: Glyoxalase-I (GLO-I) is a component of the ubiquitous detoxification system involved in the conversion of methylglyoxal (MG) to d-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.
authors.affiliation: a Department of Biochemistry , Panjab University , Chandigarh , India.
authors.forename: Aarti
authors.initials: A
authors.lastname: Yadav
authors.affiliation: b University Institute of Pharmaceutical Sciences , Panjab University , Chandigarh , India.
authors.forename: Rajnish
authors.initials: R
authors.lastname: Kumar
authors.affiliation: a Department of Biochemistry , Panjab University , Chandigarh , India.
authors.forename: Aditya
authors.initials: A
authors.lastname: Sunkaria
authors.affiliation: c Department of Food Science and Technology , National Agri-Food Biotechnology Institute , Mohali , India.
authors.forename: Nitin
authors.initials: N
authors.lastname: Singhal
authors.affiliation: b University Institute of Pharmaceutical Sciences , Panjab University , Chandigarh , India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: a Department of Biochemistry , Panjab University , Chandigarh , India.
authors.forename: Rajat
authors.initials: R
authors.lastname: Sandhir
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D007791:Lactoylglutathione Lyase
keywords: QM/MM; cancer; docking; glyoxalase-I; methylglyoxal; naringin