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

Abstract

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 $q^2\mathrm{ }$of 0.595 and $r^2$ of 0.959, while test set had $q^2$ of 0.512 and $r^2$ of 0.846. For the best comparative molecular similarity indices analysis (CoMSIA) model, its training set had $q^2$ of 0.733 and $r^2$ of 0.982, while test set had $q^2$ of 0.695 and $r^2$ 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

GRAPHIC ABSTRACT

Abbreviations
3D-QSAR	=	three-dimensional quantitative structure-activity relationship
AD	=	applicability domain
AML	=	acute myeloid leukemia
CoMFA	=	Comparative molecular field analysis
CoMSIA	=	Comparative molecular similarity indices analysis
DNMTs	=	DNA methyltransferases
E2F1	=	E2F transcription factor 1
ESP	=	Electrostatic potentials
FAD	=	Flavin adenine dinucleotide
GAFF	=	General Amber force field
H3K4	=	Histone 3 lysine 4
H3K9	=	Histone 3 lysine 9
LOO	=	Leave-one-out
LSD1	=	Lysine-specific demethylase 1
MAO-A	=	Monoamine oxidase A
MAO-B	=	Monoamine oxidase B
MAE	=	Mean absolute error
MD	=	Molecular dynamics
MLL	=	mixed lineage leukemia
MM-PBSA	=	Molecular Mechanics Poisson–Boltzmann Surface Area
PLS	=	Partial least square
PME	=	Particle Mesh Ewald
RMSD	=	Root-mean square deviation
RMSE	=	Root-mean square error
RMSF	=	Root-mean-square fluctuations
SASA	=	Solvent accessible surface area
SEE	=	Standard error of estimate
TCP	=	Tranylcypromine

Keywords:

• LSD1
• substituted pyridine derivatives
• 3D-QSAR
• molecular docking
• molecular dynamics simulations

Acknowledgements

We acknowledged the Zhengzhou university supercomputing center and college of physics engineering for the computational support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by National Natural Science Foundation of China (Project No. 81430085, No. 81172937 and No. 21372206 for H.-M. Liu.; No. 21403200 for L.-N. Ding), Ph.D. Educational Award from Ministry of Education (No. 20134101130001 for H.-M. Liu). Lina acknowledged the financial aid for International training of high-level talents in Henan (2017) from Henan Administration of Foreign Experts Affairs.