Unveiling Arformoterol as a potent LSD1 inhibitor for breast cancer treatment: A comprehensive study integrating 3D-QSAR pharmacophore modeling, molecular docking, molecular dynamics simulations and in vitro assays

Lysine Specific Demethylase 1 (LSD1) has been identified as a chromatin-modifying enzyme implicated in various cancer pathogeneses, highlighting the potential for novel epigenetic cancer treatments through the development of effective inhibitors. We employed 3D-QSAR pharmacophore modeling, molecular docking, and molecular dynamics simulations to identify a promising drug candidate for LSD1 inhibition. RMSD, RMSF, H-bond, and DSSP analysis demonstrated that ZINC02599970 (Arformoterol) and ZINC13453966 exhibited the highest LSD1 inhibitory potential. Experimental validation using MCF-7 and MDA-MB-231 cell lines revealed that Arformoterol displayed potent antiproliferative activity with IC50 values of 12.30 ± 1.48 μM and 19.69 ± 1.15 μM respectively. In contrast, the IC50 values obtained for the control (tranylcypromine) in exposure to MCF-7 and MDA-MB-231 cells were 104.6 ± 1.69 μM and 77 ± 0.67 μM, respectively. Arformoterol demonstrated greater LSD1 inhibitory potency in MCF-7 cells compared to MDA-MB-231 cells. Also, the expression of genes involved in chromatin rearrangement (LSD1), angiogenesis (VEGF1), cell migration (RORα), signal transduction (S100A8), apoptosis, and cell cycle (p53) were investigated. Arformoterol enhanced apoptosis and induced cell cycle arrest at the G2/M phase, both in MCF-7 and MDA-MB-231 cancer cells. Based on our findings, we propose that Arformoterol represents a promising candidate for breast cancer treatment, owing to its potent LSD1 inhibitory activity. •LSD1 acts as a dual transcriptional repressor and activator based on its target residue.•LSD1 directly and indirectly related to the expression of 102 genes.•Arformoterol exhibits strong LSD1 inhibitory potential (anti proliferative activity).•With availability of Arformoterol concerns about clinical trial costs is diminished.