Molecular Simulation Studies on the Binding Selectivity of Type-I Inhibitors in the Complexes with ROS1 versus ALK

• DOI: 10.1021/acs.jcim.7b00019
• Publication Date: 2017-03-20T17:47:44Z
• Authors: Yuanxin Tian; Yonghuan Yu; Yudong Shen; Hua Wan; Shan Chang; Tingting Zhang; Shanhe Wan; Jiajie Zhang
• Keywords: ALK inhibitor; Docking (animal); Binding selectivity

ROS1 and ALK are promising targets of anticancer drugs for non-small-cell lung cancer. Since they have 49% amide acid sequence homology in the kinases domain 77% identity at ATP binding area, some inhibitors also showed significant responses clinical trial, such as type-I inhibitor crizotinib PF-06463922. As a newly therapeutic target, selective is relatively rare. Moreover, molecular basis selectivity versus still remains unclear. In order to disclose preference toward over aid design inhibitors, specific interactions difference conformational changes dual ROS1/ALK systems were investigated by dynamics (MD) simulation principle component analysis (PCA) our work. Afterward, free energies (MM/GBSA) decomposition indicated that dominating effect Van der Waals interaction drives process inhibitor, residues P-loop DFG motif would play an important role selectivity. On modeling results, new designed compound 14c was verified ALK, SMU-B kinase inhibitory study. These results expected facilitate discovery rational novel inhibitors.