Insight into the binding mode of a novel LSD1 inhibitor by molecular docking and molecular dynamics simulations

Lysine-specific demethylase (LSD1) is an important enzyme for histone lysine methylation. Downregulated LSD1 expression has been linked to cancer proliferation, migration and invasion, indicating that it is an important target for anti-cancer medication. In the present study, the binding modes of a recent reported new series of LSD1 inhibitor were analyzed by using molecular docking and molecular dynamics simulations. A binding mode of these inhibitors was proposed based on the results. According to this binding mode, Thr628 can form two important hydrogen bonds with these inhibitors. Moreover, if the inhibitors can form an additional hydrogen bond with hydroxyl group of Ser289, the potency of the inhibitor can be greatly improved, such as the best inhibitor (compound 12d) in this series. Hydrophobic interactions between the inhibitors and LSD1 are also key contributor here, such as the interaction between the hydrophobic groups (benzene rings) of the inhibitors and the hydrophobic residues of LSD1 (including Val288, Val317, Val811, Ala814, Leu659, Trp751 and Tyr761). Based on the results and analysis, it may provide some useful information for future novel LSD1 inhibitor design.