Identification of Novel Selective Lysine-Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore-Based Virtual Screening Combined with Docking

Chen Zhou; Di Kang; Yungen Xu; Luyong Zhang; Xiaoming Zha

doi:10.1111/cbdd.12461

Identification of Novel Selective Lysine-Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore-Based Virtual Screening Combined with Docking

Chem Biol Drug Des. 2015 Jun;85(6):659-71. doi: 10.1111/cbdd.12461. Epub 2014 Dec 22.

Authors

Chen Zhou^{1

2

3}, Di Kang^{1

2

3}, Yungen Xu^{1

3}, Luyong Zhang^{1

2}, Xiaoming Zha^{1

2}

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
² Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.

PMID: 25346381
DOI: 10.1111/cbdd.12461

Abstract

Lysine-specific demethylase 1 (LSD1) plays an important role in regulating the lysine methylation at residues K4 and K9 on histone H3. High levels of LSD1 expression have been observed in several malignant tumors. In this study, we presented a pharmacophore-based virtual screening of a moderate database of 171 143 small molecules. A pharmacophore of LSD1 inhibitors was constructed for the first time and then used to screen the compound library combined with validated molecular docking tools followed by biochemical assays, led to the identification of 9 novel LSD1 inhibitors, showing their IC50 values in a range of 2.41-101 μm. Furthermore, compound XZ09 exhibited less inhibition against the homologous monoamine oxidase A (MAO-A) and B (MAO-B) displaying its moderate selectivity. Our study provides an effective virtual screening method to identify new LSD1 inhibitors and XZ09 represents a potent and selective lead compound to deserve further optimization for the treatment of LSD1 overexpressing cancers.

Keywords: LSD1 inhibitors; docking; pharmacophore; selective; virtual screening.

Publication types

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

MeSH terms

Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Histone Demethylases / antagonists & inhibitors*
Histone Demethylases / chemistry
Histone Demethylases / metabolism
Humans
Molecular Docking Simulation
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology
Small Molecule Libraries / chemistry*
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Monoamine Oxidase Inhibitors
Small Molecule Libraries
Histone Demethylases
Monoamine Oxidase
KDM1A protein, human