Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors

RET (rearranged during transfection) kinase, one of the receptor tyrosine kinases, plays a crucial role in the development of the human nervous system. It is also involved in various cell signaling networks responsible for the normal cell division, growth, migration, and survival. Previously reported clinical studies revealed that deregulation or aberrant activation of RET signaling can cause several types of human cancer. For example, medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia (MEN2A, MEN2B) occur due to sporadic mutation or germline RET mutation. A number of RET kinase inhibitors have been approved by the FDA for the treatment of cancer, such as cabozantinib, vandetanib, lenvatinib, and sorafenib. However, each of these drugs is a multikinase inhibitor. Hence, RET is an important therapeutic target for cancer drug design. In this work, we have performed various molecular modelling studies, such as molecular docking and dynamics simulation for the most active compound of the pyrazole series as RET kinase inhibitors. Furthermore, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) free energy calculation and 3-dimensional quantitative structure-activity relationship (3D-QSAR) were performed using g_mmpbsa and SYBYL-X 2.1 package. The results of this study revealed the crucial binding site residues at the active site of RET kinase and contour map analysis showed important structural characteristics for the design of new highly active inhibitors. Therefore, we have designed ten RET kinase inhibitors, which showed higher inhibitory activity than the most active compound of the series. The results of our study provide insights to design more potent and selective RET kinase inhibitors.