Probing the binding mechanism of substituted pyridine derivatives as effective and selective lysine-specific demethylase 1 inhibitors using 3D-QSAR, molecular docking and molecular dynamics simulations
Lysine-specific demethylase 1 (LSD1) was regarded as a promising anticancer target for the novel drug discovery. In this work, we carried out a molecular modeling study on the substituted pyridine derivatives as LSD1 inhibitors using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations. Molecular docking studies predicted the probable binding mode of ligands, and suggested Lys661 and Asp555 might be key residues. Our 3D-QSAR models exhibited satisfactory internal and external predicted capacity. For the comparative molecular field analysis (CoMFA) model, its training set had of 0.595 and of 0.959, while test set had of 0.512 and of 0.846. For the best comparative molecular similarity indices analysis (CoMSIA) model, its training set had of 0.733 and of 0.982, while test set had of 0.695 and of 0.922. MD simulations result revealed the detailed binding process and found an important conserved water-bridge motif between ligands and protein. The binding free energies calculation using Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) approach coincided well with the experimental bioactivity and demonstrated that the electrostatic interaction was the major driving force for binding. The energy decomposition pointed out some significant residues (Asp555, Lys661, Trp695, Tyr761 and FAD) for the LSD1 potency increase. Based on these results, five new inhibitors were designed, and their activities were predicted using our 3D-QSAR models.
Communicated by Ramaswamy H. Sarma
Abbreviations3D-QSAR
three-dimensional quantitative structure-activity relationship
ADapplicability domain
AMLacute myeloid leukemia
CoMFAComparative molecular field analysis
CoMSIAComparative molecular similarity indices analysis
DNMTsDNA methyltransferases
E2F1E2F transcription factor 1
ESPElectrostatic potentials
FADFlavin adenine dinucleotide
GAFFGeneral Amber force field
H3K4Histone 3 lysine 4
H3K9Histone 3 lysine 9
LOOLeave-one-out
LSD1Lysine-specific demethylase 1
MAO-AMonoamine oxidase A
MAO-BMonoamine oxidase B
MAEMean absolute error
MDMolecular dynamics
MLLmixed lineage leukemia
MM-PBSAMolecular Mechanics Poisson–Boltzmann Surface Area
PLSPartial least square
PMEParticle Mesh Ewald
RMSDRoot-mean square deviation
RMSERoot-mean square error
RMSFRoot-mean-square fluctuations
SASASolvent accessible surface area
SEEStandard error of estimate
TCPTranylcypromine
three-dimensional quantitative structure-activity relationship
applicability domain
acute myeloid leukemia
Comparative molecular field analysis
Comparative molecular similarity indices analysis
DNA methyltransferases
E2F transcription factor 1
Electrostatic potentials
Flavin adenine dinucleotide
General Amber force field
Histone 3 lysine 4
Histone 3 lysine 9
Leave-one-out
Lysine-specific demethylase 1
Monoamine oxidase A
Monoamine oxidase B
Mean absolute error
Molecular dynamics
mixed lineage leukemia
Molecular Mechanics Poisson–Boltzmann Surface Area
Partial least square
Particle Mesh Ewald
Root-mean square deviation
Root-mean square error
Root-mean-square fluctuations
Solvent accessible surface area
Standard error of estimate
Tranylcypromine