Investigating the binding mechanism of (4-Cyanophenyl)glycine derivatives as reversible LSD1 by 3D-QSAR, molecular docking and molecular dynamics simulations

Abstract

Lysine specific demethylase 1 (LSD1) have been regard as an important drug target on the therapy of cancer and leukemia. However, the development of effective reversible LSD1 inhibitors was facing many challenges. In this work, we carried out a molecular modeling study on (4-Cyanophenyl)glycine derivatives as reversible LSD1 inhibitors using 3D-QSAR, molecular docking and molecular dynamics simulations. Molecular docking study revealed the possible binding mechanism of these inhibitors with LSD1. We used comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to generate 3D-QSAR models. The results showed that our CoMFA model had q2 of 0.785, r2 = 0.994 and r2pred of 0.92, while the best CoMSIA model had q2 of 0.746, r2 = 0.985 and r2pred of 0.86. Molecular dynamics simulations validated the rationality of docking results and predicted the detailed interactions between the ligands and LSD1. An important hydrogen bond network was discovered though MD simulation. Some key residues (FAD, Asp555, Gln358, Tyr761, Lys661 and Trp695) were pointed out after the binding free energy calculation using MM-PBSA method. We hope these result could provide useful information for our further design of potent and selective LSD1 inhibitors.