Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation

Minghao Luo; Hui Wang; Yi Zou; Shengping Zhang; Jianhu Xiao; Guangde Jiang; Yihua Zhang; Yisheng Lai

doi:10.1016/j.jmgm.2016.06.011

Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation

J Mol Graph Model. 2016 Jul:68:128-139. doi: 10.1016/j.jmgm.2016.06.011. Epub 2016 Jun 18.

Authors

Minghao Luo¹, Hui Wang¹, Yi Zou¹, Shengping Zhang², Jianhu Xiao¹, Guangde Jiang³, Yihua Zhang¹, Yisheng Lai⁴

Affiliations

¹ 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.
² School of Chemical Sciences, The University of Auckland, 23 Symonds St., Auckland 1142, New Zealand.
³ Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA.
⁴ 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.

PMID: 27434826
DOI: 10.1016/j.jmgm.2016.06.011

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.

Keywords: Binding free energy; DOT1L inhibitor; Docking; Molecular dynamic simulation; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides / chemistry
Acetamides / pharmacology*
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Methyltransferases / antagonists & inhibitors*
Methyltransferases / chemistry
Molecular Docking Simulation*
Molecular Dynamics Simulation*
Mutant Proteins / chemistry
ROC Curve
Thermodynamics
User-Computer Interface

Substances

Acetamides
Enzyme Inhibitors
Mutant Proteins
Methyltransferases