Molecular Dynamics Simulations of the Interactions between Glial Cell Line-Derived Neurotrophic Factor Family Receptor GFRα1 and Small-Molecule Ligands

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) support the survival and functioning of various neuronal populations. Thus, they could be attractive therapeutic agents against a multitude of neurodegenerative diseases caused by progressive death of GFLs responsive neurons. Small-molecule ligands BT13 and BT18 show an effect on GDNF family receptor GFR alpha 1 and RET receptor tyrosine kinase RetA function. Thus, their potential binding sites and interactions were explored in the GDNF-GFR alpha 1-RetA complex using molecular docking calculations as well as molecular dynamics (MD) simulations. Three possible regions were examined: the interface between GDNF and GFR alpha 1 (region A), the RetA interface with GFR alpha 1 (region B), and a possible allosteric site in GFR alpha 1 (region C). The results obtained by the docking calculations and the MD simulations indicate that the preferable binding occurs at the allosteric site. A less preferable binding site was detected on the RetA surface interfacing GFR alpha 1. In the membrane-bound state of RetA this can enable compounds BT13 and BT18 to act as direct RetA agonists. The analysis of the MD simulations shows hydrogen bonds for BT13 and significant hydrophobic interactions with GFR alpha 1 for BT13 and BT18 at the allosteric site.