Identification of 2,4-diarylaminopyrimidine analogues as ALK inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations

Anaplastic lymphoma kinase (ALK) is a particularly promising target for the development of small molecule anti-cancer drugs. In the present study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 60 ALK inhibitors to build three-dimensional quantitative structure–activity relationship models. Both the ligand-based resultants of CoMFA (r 2 0.970, q 2 0.660) and CoMSIA (r 2 0.979, q 2 0.623) models exhibited good predictability. The resulting contour maps illustrated the regions where interactive fields may affect the activity. Molecular docking was then performed to explore the interactions between these inhibitors and the ALK-4DCE protein. A few key residues (His32, Gly31, Gly169, Asp170, Val35, Ala100, Pro160, Lys50, and Leu30) at the binding site of 4DCE were identified. Molecular dynamics simulation further verified the reliability. The information acquired in this work not only provides a better appreciation of interactions between these molecules and the ALK receptor but could also be applied to design more effective ALK inhibitors.