Computational analysis of binding between benzamide-based derivatives and Abl wt and T315I mutant kinases

Abstract

With the aim of discovering new mutation-resistant Abl inhibitors, especially the most difficult to overcome T315I mutant, the interactions between Abl kinases and a series of benzamide-based derivatives were studied using a combined method of a three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulation. The results show that optimum CoMSIA (comparative molecular similarity index analysis) models have satisfactory internal and external predicted capacity, and the differences of structural features between Abl wt and T315I mutant inhibitors can be well pinpointed by the CoMSIA field plots. The detailed binding process and the in depth comparison of the binding modes of compounds with different activities against both kinases were validated by MD simulation. The binding free energies coincided well with the experimental bioactivities. The energy decomposition demonstrated that the van del Waals interaction is the major driving force for binding, and the hydrogen bond interactions with Met318 and Glu286 are also significant for the Abl potency increase. Finally, the most crucial residues impacting the strong interactions are also identified. These results can provide helpful reference for finding novel potential inhibitors.