Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation.

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure-activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q = 0.778, Rpred2 = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q = 0.764, Rpred2 = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (, , and ) and the template molecule were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that , , and performed better than template molecule due to the introduction of the amino and hydrophobic groups, especially for the and , which will provide guidance for the design of LSD1 inhibitors.