LSD1-Based Reversible Inhibitors Virtual Screening and Binding Mechanism Computational Study

As one of the crucial targets epigenetics, histone lysine-specific demethylase 1 (LSD1) is significant in occurrence and development various tumors. Although several irreversible covalent LSD1 inhibitors have entered clinical trials, large size polarity FAD-binding pocket undesired toxicity focused interest on developing reversible inhibitors. In this study, targeting substrate-binding LSD1, structure-based ligand-based virtual screenings were adopted to expand potential novel structures with molecular docking pharmacophore model strategies, respectively. Through drug-likeness evaluation, ADMET screening, dynamics simulations, binding free energy we screened out four hit compounds from databases 2,029,554 compounds, Generally, these can be divided into two categories, amide (Lig2 Comp2) 1,2,4-triazolo-4,3-α-quinazoline (Comp3, Comp4, Comp7). Among them, Comp4 exhibits strongest affinity. Finally, mechanisms further calculated detail by residue decomposition. It was found that van der Waals interactions contribute most binding, FAD also helpful stabilizing avoiding off-target effects. We believe work not only provides a solid theoretical foundation for design substrate inhibitors, but expands diversity parent nucleus, offering new insights synthetic chemists.