title: Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation.
abstract: Dot1-like protein (DOT1L) is a histone methyltransferase that has become a novel and promising target for acute leukemias bearing mixed lineage leukemia (MLL) gene rearrangements. In this study, a hierarchical docking-based virtual screening combined with molecular dynamic (MD) simulation was performed to identify DOT1L inhibitors with novel scaffolds. Consequently, 8 top-ranked hits were eventually identified and were further subjected to MD simulation. It was indicated that all hits could reach equilibrium with DOT1L in the MD simulation and further binding free energy calculations suggested that phenoxyacetamide-derived hits such as L01, L03, L04 and L05 exhibited remarkably higher binding affinity compared to other hits. Among them, L03 showed both the lowest glide score (-12.281) and the most favorable binding free energy (-303.9+/-16.5kJ/mol), thereby making it a promising lead for further optimization.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Minghao
authors.initials: M
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zou
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds St., Auckland 1142, New Zealand.
authors.forename: Shengping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jianhu
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA.
authors.forename: Guangde
authors.initials: G
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yslai@cpu.edu.cn.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry; D012372:ROC Curve; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; D050505:Mutant Proteins; D008780:Methyltransferases
keywords: Binding free energy; DOT1L inhibitor; Docking; Molecular dynamic simulation; Virtual screening