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

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.