| dc.description.abstract | Epidermal growth factor receptor (EGFR) inhibitors interrupt EGFR-dependent cellular signaling pathways that lead to accelerated cancerous tumor growth and proliferation, and are actively developed for treatment of various types of non-small cell cancer. Here, we continue our investigation of an empirical chirality-potency relationship between the R/S enantiomers of thieno-, pyrrolo- and furopyrmidines when acting as Type I Epidermal Growth Factor Receptor Tyrosine Kinase (EGFR-TK) inhibitors, with the aim of providing a mechanism which relates molecular chirality to empirical measurements of inhibition.
Based on long Molecular Synamics simulations (\SI{1}{\micro\second}) of ligand-in-receptor complexes between the active EGFR intracellular domain and inhibitors, we present qualitative evidence that the primary differentiator of potency is a combination of 3 stereo-specific interactions: a water-mediated hydrogen bond to Threonine-854, a pi-cation interaction with Lysine-745, and for methanol-containing inhibitors, a hydrogen bond to either Lysine-745 or Aspartate-855. These interactions are shown to occur more frequently for the high-potency enantiomers in our simulation. The water-bridge is a new addition which we previously couldn't have modeled in our gas-state simulation.
Our findings provide important insight for the design of EGFR inhibitors. More broadly, the results raise further questions about the role of water in ligand-receptor bonding, and add to a growing list of evidence that modeling of water is crucial in estimating the binding affinity of small molecule inhibitors. | |
