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 q2 of 0.595 and r2 of 0.959, while test set had q2 of 0.512 and r2 of 0.846. For the best comparative molecular similarity indices analysis (CoMSIA) model, its training set had q2 of 0.733 and r2 of 0.982, while test set had q2 of 0.695 and r2 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

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

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