Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase
Swapnil P Bhujbal1, Seketoulie Keretsu1, Seung Joo Cho1,2
1Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju 501-759, Korea.
Abstract:
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.
Insights
This study identifies key binding site residues in RET kinase, leading to the design of novel, potent RET kinase inhibitors for cancer therapy. These findings offer insights for developing more effective and selective cancer drugs targeting RET signaling pathways.
Area of Science:
- Medicinal Chemistry
- Computational Biology
- Oncology
Background:
- Rearranged during transfection (RET) kinase is vital for nervous system development and cell signaling.
- Aberrant RET signaling drives various cancers, including medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia (MEN2A, MEN2B).
- Existing FDA-approved RET inhibitors are multi-targeted, highlighting the need for selective RET inhibitors.
Purpose of the Study:
- To perform molecular modeling studies on pyrazole-based compounds as RET kinase inhibitors.
- To identify crucial binding site residues and structural characteristics for enhanced RET inhibitor design.
- To design novel RET kinase inhibitors with improved potency and selectivity.
Main Methods:
- Molecular docking and dynamics simulations were employed.
- Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) free energy calculations were conducted.
- 3-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed using SYBYL-X 2.1.
Main Results:
- Key RET kinase active site residues crucial for inhibition were identified.
- Contour map analysis revealed important structural features for inhibitor design.
- Ten novel RET kinase inhibitors were designed, exhibiting higher inhibitory activity than the lead compound.
Conclusions:
- The study provides valuable insights into the structural requirements for potent and selective RET kinase inhibition.
- Designed inhibitors demonstrate potential for improved cancer therapeutics targeting RET signaling.
- This research facilitates the development of next-generation RET-targeted cancer drugs.
