Issue 2, 2015

Studies of N9-arenthenyl purines as novel DFG-in and DFG-out dual Src/Abl inhibitors using 3D-QSAR, docking and molecular dynamics simulations

Abstract

Recently, the development of Src/Abl (c-Src/Bcr–Abl tyrosine kinases) dual inhibitors has attracted considerable attention from the research community for treatment of malignancies. In order to explore the different structural features impacting the Src and Abl inhibitory activities of N9-arenethenyl purines and to investigate the molecular mechanisms of ligand–receptor interactions, a molecular modeling study combining the three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations was performed. The obtained CoMFA (comparative molecular field analysis) models exhibited satisfactory internal and external predictability. The plots of the CoMFA fields could be used to investigate the structural differences between DFG-in (targeting the active enzyme conformation) and DFG-out (targeting the inactive enzyme conformation) inhibitors. The key amino acid residues were identified by docking studies, and the detailed binding modes of the compounds with different activities were determined by MD simulations. The binding free energies gave a good correlation with the experimental determined activities. In an energetic analysis, the MM-PBSA (molecular mechanics Poisson–Boltzmann surface) energy decomposition revealed that the van der Waals interactions were the major driving force for the binding of the DFG-in and DFG-out compounds to Src and Abl, especially the hydrophobic interactions between ligands and residues Ala403/380, Asp404/381, and Phe405/382 in DFG-out Src and Abl complexes. They also help to stabilize the DFG-out conformations. These results can offer useful references for designing novel potential DFG-in and DFG-out dual Src/Abl inhibitors.

Graphical abstract: Studies of N9-arenthenyl purines as novel DFG-in and DFG-out dual Src/Abl inhibitors using 3D-QSAR, docking and molecular dynamics simulations

Supplementary files

Article information

Article type
Paper
Submitted
12 Jun 2014
Accepted
21 Oct 2014
First published
21 Oct 2014

Mol. BioSyst., 2015,11, 394-406

Studies of N9-arenthenyl purines as novel DFG-in and DFG-out dual Src/Abl inhibitors using 3D-QSAR, docking and molecular dynamics simulations

S. Ma, G. Zeng, D. Fang, J. Wang, W. Wu, W. Xie, S. Tan and K. Zheng, Mol. BioSyst., 2015, 11, 394 DOI: 10.1039/C4MB00350K

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements