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Identification of Novel Selective Lysine‐Specific Demethylase 1 ( LSD 1) Inhibitors Using a Pharmacophore‐Based Virtual Screening Combined with Docking
Author(s) -
Zhou Chen,
Kang Di,
Xu Yungen,
Zhang Luyong,
Zha Xiaoming
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12461
Subject(s) - pharmacophore , virtual screening , demethylase , chemistry , docking (animal) , computational biology , small molecule , histone , biochemistry , biology , medicine , gene , nursing
Lysine‐specific demethylase 1 ( LSD 1) plays an important role in regulating the lysine methylation at residues K 4 and K 9 on histone H 3. High levels of LSD 1 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 LSD 1 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 LSD 1 inhibitors, showing their IC 50 values in a range of 2.41–101 μ m . Furthermore, compound XZ 09 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 LSD 1 inhibitors and XZ09 represents a potent and selective lead compound to deserve further optimization for the treatment of LSD 1 overexpressing cancers.