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

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