1 research outputs found
Molecular Simulation Studies on the Binding Selectivity of Type‑I Inhibitors in the Complexes with ROS1 versus ALK
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 and 77% identity at the ATP binding area, some ALK
inhibitors also showed some significant responses for ROS1 in the
clinical trial, such as the type-I binding inhibitor crizotinib and
PF-06463922. As a newly therapeutic target, the selective ROS1 inhibitor
is relatively rare. Moreover, the molecular basis for the selectivity
of ROS1 versus ALK still remains unclear. In order to disclose the
binding preference toward ROS1 over ALK and to aid the design of selective
ROS1 inhibitors, the specific interactions and difference of conformational
changes in the dual and selective ROS1/ALK inhibitors systems were
investigated by molecular dynamics (MD) simulation and principle component
analysis (PCA) in our work. Afterward, binding free energies (MM/GBSA)
and binding free energies decomposition analysis indicated that the
dominating effect of Van der Waals interaction drives the specific
binding process of the type-I inhibitor, and residues of the P-loop
and the DFG motif would play an important role in selectivity. On
the basis of the modeling results, the new designed compound <b>14c</b> was verified as a selective ROS1 inhibitor versus ALK,
and SMU-B was a dual ROS1/ALK inhibitor by the kinase inhibitory study.
These results are expected to facilitate the discovery and rational
design of novel and specific ROS1 inhibitors