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Published on: May 20, 2020
In Silico Identification of 2,4-Diaryl-6-styrylpyridine Derivatives as Orthosteric-allosteric EGFR Inhibitors
Harizal -1,2, Jumina -1, Harno Dwi Pranowo1
1Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta, 55281, Indonesia.
Background:
Epidermal growth factor receptor tyrosine kinase (EGFR TK) is a primary target for inhibiting cellular signal transduction in several types of cancer. Numerous EGFR TK inhibitors have been developed and approved as standard therapy for cancer management. However, the development of drug resistance and significant adverse effects have encouraged the search for alternative EGFR TK inhibitors.
Objective:
This study attempted to identify 2,4-diaryl-6-styrylpyridine derivatives as alternative orthosteric-allosteric EGFR TK inhibitors through molecular docking, molecular dynamic simulation, binding free energy calculation, and pharmacokinetic properties analysis.
Methods:
Two series of 2,4-diaryl-6-styrylpyridine derivatives were docked in orthosteric and allosteric sites of EGFR TK. Docking results were validated through molecular dynamic simulation and binding free energy calculation using YASARA Structure. Pharmacokinetic properties were analyzed using web-based free servers SwissADME and ADMETLab 3.0.
Results:
The molecular docking studies revealed relatively strong affinity, with binding energy ranging from -10.2 to -12.2 kcal/mol in the orthosteric site and from -7.7 to -10.9 kcal/mol in the allosteric site of EGFR TK. The proposed ligand complexes with the highest binding energy and proper hydrogen bonds showed comparable stability and binding free energy than native ligand complexes. The pharmacokinetic properties of the proposed ligands indicated relatively poor characteristics due to relatively high lipophilicity and certain toxicophores.
Conclusion:
This study identified NASP06 and NASP01 as the most stable orthosteric and allosteric inhibitors of EGFR TK, respectively. These findings revealed a novel class of EGFR TK inhibitors capable of interacting with both orthosteric and allosteric sites.
Insights
Researchers identified novel 2,4-diaryl-6-styrylpyridine derivatives as potential dual orthosteric-allosteric inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR TK). NASP06 and NASP01 show promise for overcoming resistance and improving cancer therapy.
Area of Science:
- Medicinal Chemistry
- Computational Drug Design
- Cancer Therapeutics
Background:
- Epidermal growth factor receptor tyrosine kinase (EGFR TK) is a key target in cancer therapy.
- Existing EGFR TK inhibitors face challenges with drug resistance and adverse effects.
- There is a need for novel inhibitors targeting both orthosteric and allosteric sites.
Purpose of the Study:
- To identify 2,4-diaryl-6-styrylpyridine derivatives as alternative EGFR TK inhibitors.
- To investigate their potential as dual orthosteric-allosteric inhibitors.
- To evaluate binding affinity, stability, and pharmacokinetic properties.
Main Methods:
- Molecular docking into orthosteric and allosteric EGFR TK sites.
- Molecular dynamic simulations and binding free energy calculations (YASARA Structure).
- Pharmacokinetic property analysis (SwissADME, ADMETLab 3.0).
Main Results:
- High binding affinity observed, with binding energies ranging from -8.3 to -12.2 kcal/mol.
- Proposed ligands demonstrated stability comparable to native ligands.
- Identified pharmacokinetic limitations including high lipophilicity and toxicophores.
Conclusions:
- NASP06 and NASP01 identified as potent orthosteric and allosteric EGFR TK inhibitors, respectively.
- These compounds represent a novel class of dual-acting EGFR TK inhibitors.
- Further optimization is needed to address pharmacokinetic challenges.
