Discovery of new potent lysine specific histone demythelase-1 inhibitors (LSD-1) using structure based and ligand based molecular modelling and machine learning

Lysine-specific histone demethylase 1 (LSD-1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 and is highly overexpressed in different types of cancer. Therefore, it has been widely recognized as a promising therapeutic target for cancer therapy. Towards this end, we employed various Computer Aided Drug Design (CADD) approaches including pharmacophore modelling and machine learning. Pharmacophores generated by structure-based (SB) (either crystallographic-based or docking-based) and ligand-based (LB) (either supervised or unsupervised) modelling methods were allowed to compete within the context of genetic algorithm/machine learning and were assessed by Shapley additive explanation values (SHAP) to end up with three successful pharmacophores that were used to screen the National Cancer Institute (NCI) database. Seventy-five NCI hits were tested for their LSD-1 inhibitory properties against neuroblastoma SH-SY5Y cells, pancreatic carcinoma Panc-1 cells, glioblastoma U-87 MG cells and in vitro enzymatic assay, culminating in 3 nanomolar LSD-1 inhibitors of novel chemotypes. Structure-based and ligand-based pharmacophores were allowed to compete within genetic algorithm/machine learning to yield three pharmacophores. Subsequent virtual screening identified three nanomolar LSD-1 inhibitors.