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Published on: April 6, 2016
Novel EGFR (T790M)-cMET dual inhibitors: putative therapeutic agents for non-small-cell lung cancer
Pankaj Kumar Singh1, Om Silakari1
1Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug research, Punjabi University, Patiala, Punjab 147002, India.
Aim:
Different resistance mechanisms, especially, T790M secondary acquired point mutation and in some cases amplification of cMET, have been a major setback for the lung cancer therapies.
Methodology:
The current in silico study explored the small molecules which can act as putative EGFR (T790M)-cMET dual inhibitors. Databases were first filtered and subsequently cross filtered, initially by thoroughly validated pharmacophore models for both targets. As per score and interactions obtained in docking, the molecules were subjected to molecular dynamics simulations, to study the stability and binding orientations of their complexes with target proteins.
Conclusion:
Molecular dynamics simulations predicted three hits to possess good binding affinities and stability for EGFR (T790M) and cMET, which can be claimed to be potential dual inhibitors.
Insights
Researchers identified potential dual inhibitors for lung cancer therapy. These small molecules target both epidermal growth factor receptor (EGFR) T790M mutations and cMET, overcoming resistance mechanisms.
Area of Science:
- Oncology
- Computational Chemistry
- Drug Discovery
Background:
- Lung cancer therapies face setbacks due to resistance mechanisms like EGFR (T790M) mutations and cMET amplification.
- Developing effective treatments requires targeting these specific resistance pathways.
Purpose of the Study:
- To explore small molecules that can act as dual inhibitors for EGFR (T790M) and cMET.
- To identify potential drug candidates for overcoming lung cancer resistance.
Main Methods:
- In silico screening of databases using validated pharmacophore models for EGFR (T790M) and cMET.
- Molecular docking to assess binding scores and interactions.
- Molecular dynamics simulations to evaluate complex stability and binding orientations.
Main Results:
- Three small molecules demonstrated good binding affinities and stability against both EGFR (T790M) and cMET.
- These compounds show promise as potential dual inhibitors.
Conclusions:
- The identified molecules are potential candidates for dual inhibition of EGFR (T790M) and cMET.
- This study provides a foundation for developing novel lung cancer therapies targeting resistance mechanisms.
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