In Silico Identification of 2,4-Diaryl-6-styrylpyridine Derivatives as Orthosteric-Allosteric EGFR Inhibitors.

Abstract

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 -10.3 to -12.2 kcal/mol in the orthosteric site and from -8.3 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.