title: Novel flavonol analogues as potential inhibitors of JMJD3 histone demethylase-A study based on molecular modelling.
abstract: Epigenetic modulation of gene expression has drawn enormous attention among researchers globally in the present scenario. Since their discovery, Jmj-C histone demethylases were identified as useful markers in understanding the role of epigenetics in inflammatory conditions and in cancer as well. This has created arousal of interest in search of suitable candidates. Potential inhibitors from various other scaffolds such as hydroxyquinolines, hydroxamic acids and triazolopyridines have already been identified and reported. In this direction, our present study attempts to target one of the important members of the family- namely JMJD3 (also known as KDM6B), that plays a pivotal role in inflammatory and immune reactions. Using molecular modeling approaches, myricetin analogues were identified as promising inhibitors of JMJD3. Extensive literature review showed myricetin as the most promising flavonol inhibitor for this enzyme. It served as a prototype for our study and modification of it's scaffold led to generation of analogues. The ZINC database was used as a repository for natural compounds and their analogues. Using similarity search options, 65 analogues of myricetin were identified and screened against JMJD3 (PDB ID: 4ASK), using the high throughput virtual screening and ligand docking tools in Maestro Molecular Modeling platform (version 10.5) from Schrödinger, LLC. 8 analogues out of 65 were identified as the most appropriate candidates which gave the best pose in ligand docking. Their binding mode and energy calculations were analysed using induced fit docking (IFD) and prime-MMGBSA tool, respectively. Thus, our findings highlight the most promising analogues of myricetin with comparable binding affinity as well as binding energy than their counterparts that could be taken for further optimisation as inhibitors of JMJD3 in both in vitro and in vivo screening studies.
authors.affiliation: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, 576104, India.
authors.forename: Sanchari
authors.initials: S
authors.lastname: Basu Mallik
authors.affiliation: Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, 576104, India.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Pai
authors.affiliation: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, 576104, India.
authors.forename: Rekha R
authors.initials: RR
authors.lastname: Shenoy
authors.affiliation: Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, 576104, India. Electronic address: bs.jayashree@manipal.edu.
authors.forename: B S
authors.initials: BS
authors.lastname: Jayashree
mesh_terms: D055162:Biocatalysis; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D013816:Thermodynamics
chemical_list: D005419:Flavonoids; D007656:Ketoglutaric Acids; D008024:Ligands; C040015:myricetin; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human
keywords: Epigenetics; JMJD3; Ligand docking; Myricetin; Natural flavonols