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.
Molecules (Basel, Switzerland)
|February 2, 2021
Summary
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.
