Molecular modeling study on Mer kinase inhibitors using 3D-QSAR and docking approaches

Abstract

Mer kinase is a novel cancer therapeutic target. Abnormal activation or overexpression of Mer kinase has been implicated in several human cancers. Three-dimensional quantitative structure–activity relationship (3D-QSAR) and molecular docking studies were performed on a series of pyridinepyrimidine derivatives to understand the structural basis for Mer kinase inhibitory activity. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used to derive 3D-QSAR models. The CoMFA model produced statistically significant results with a cross-validated correlation coefficient (q 2) of 0.634 and a non-cross-validated correlation coefficient (r 2) of 0.968. The reliable CoMSIA model with q 2 of 0.665 and r 2 of 0.991 was obtained from the combination of steric, electrostatic, hydrophobic, hydrogen bond acceptor and hydrogen bond donor fields. The CoMFA and CoMSIA models showed reasonable predictive abilities with predicted correlation coefficient (r pred 2 ) of 0.629 and 0.811, respectively. The models were further evaluated by leave-five-out cross-validation and bootstrapping analyses. Docking studies were carried out to deduce probable binding conformations of this series of inhibitors inside the active site of Mer kinase. Docking studies also contributed to the identification of some crucial binding residues in the active site. The correlation of 3D-QSAR and docking results indicated the robustness of the QSAR models. Overall, a combined application of docking and 3D-QSAR results could provide a better understanding of the interactions between the inhibitors and protein. This study could assist in the design of novel compounds with enhanced Mer kinase inhibitory activity.