flavin-adenine-dinucleotide and 3-methylxanthine

Lysine-specific demethylase 1 (LSD1) has been reported to connect with a range of solid tumors. Thus, the exploration of LSD1 inhibitors has emerged as an effective strategy for cancer treatment. In this study, we constructed a pharmacophore model based on a series of flavin adenine dinucleotide (FAD)-competing inhibitors bearing triazole - dithiocarbamate scaffold combining docking, structure-activity relationship (SAR) study, and molecular dynamic (MD) simulation. Meanwhile, another pharmacophore model was also constructed manually, relying on several speculated substrate-competing inhibitors and reported putative vital interactions with LSD1. On the basis of the two pharmacophore models, multi-step virtual screenings (VSs) were performed against substrate-binding pocket and FAD-binding pocket, respectively, combining pharmacophore-based and structure-based strategy to exploit novel LSD1 inhibitors. After bioassay evaluation, four compounds among 21 hits with diverse and novel scaffolds exhibited inhibition activity at the range of 3.63-101.43 μM. Furthermore, substructure-based enrichment was performed, and four compounds with a more potent activity were identified. After that, the time-dependent assay proved that the most potent compound with IC

Topics: Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Discovery; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Flavin-Adenine Dinucleotide; Histone Demethylases; Histones; Humans; Inhibitory Concentration 50; Models, Chemical; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Conformation; Stomach Neoplasms; Structure-Activity Relationship; Triazoles; Xanthines