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Computational Simulation Study of Potential Inhibition of c-Met Kinase Receptor by Phenoxy pyridine Derivatives:
Li-Yuan Guo1,2, Yu-Lu Yang1,2, Jian-Bo Tong1,2
1College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China.
Abstract:
The mesenchymal-epithelial transition factor (c-Met) is a tyrosine kinase receptor protein, and excessive cell transformation can lead to cancer. Therefore, there is an urgent need to develop novel receptor tyrosine kinase inhibitors by inhibiting the activity of c-Met protein. In this study, 41 compounds are selected from the reported literature, and the interactions between phenoxy pyridine derivatives and tumor-associated proteins are systematically investigated using a series of computer-assisted drug design (CADD) methods, aiming to predict potential c-Met inhibitors with high activity. The Topomer CoMFA (q2=0.620, R2=0.837) and HQSAR (q2=0.684, R2=0.877) models demonstrate a high level of robustness. Further internal and external validation assessments show high applicability and accuracy. Based on the results of the Topomer CoMFA model, structural fragments with higher contribution values are identified and randomly combined using a fragment splice technique, result in a total of 20 compounds with predicted activities higher than the template molecules. Molecular docking results show that these compounds have good interactions and van der Waals forces with the target proteins. The results of molecular dynamics and ADMET predictions indicate that compounds Y4, Y5, and Y14 have potential as c-Met inhibitors. Among them, compound Y14 exhibits superior stability with a binding free energy of -165.18 KJ/mol. These studies provide a reference for the future design and development of novel compounds with c-Met inhibitory activity.
Insights
Novel phenoxy pyridine derivatives were identified as potential c-Met inhibitors for cancer therapy. Computer-assisted drug design predicted and validated compounds with high activity and stability against tumor-associated proteins.
Area of Science:
- Medicinal Chemistry
- Computational Drug Discovery
- Oncology
Background:
- The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase implicated in cancer progression.
- Developing novel c-Met inhibitors is crucial for effective cancer treatment.
- Targeting c-Met activity offers a promising therapeutic strategy.
Purpose of the Study:
- To identify and design novel phenoxy pyridine derivatives as potent c-Met inhibitors.
- To systematically investigate the interactions between these derivatives and tumor-associated proteins.
- To predict and validate potential drug candidates using computational methods.
Main Methods:
- Utilized computer-assisted drug design (CADD) including Topomer CoMFA and HQSAR for quantitative structure-activity relationship (QSAR) modeling.
- Employed fragment-based drug design by combining structural fragments to generate new compounds.
- Performed molecular docking, molecular dynamics, and ADMET predictions for validation.
Main Results:
- Developed robust Topomer CoMFA (q²=0.620, R²=0.837) and HQSAR (q²=0.684, R²=0.877) models.
- Generated 20 novel compounds with predicted activities superior to template molecules.
- Identified compounds Y4, Y5, and Y14 as promising c-Met inhibitors, with Y14 showing exceptional stability (-165.18 kJ/mol binding free energy).
Conclusions:
- The study successfully identified potential c-Met inhibitors through integrated CADD approaches.
- Compound Y14 demonstrates significant potential for further development as an anti-cancer therapeutic.
- These findings provide a valuable framework for designing future c-Met inhibitory agents.
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