Computational Studies of Liver Receptor Homolog 1 in the Presence of Small Molecule Agonists: Allosteric Communication and Virtual Screening for New Potential Drug Candidates

Abstract

Liver Receptor Homolog 1 (LRH-1) is a nuclear receptor whose dysfunction is affiliated with diseases such as diabetes and cancer. Recent investigations demonstrate that higher levels of activation and modulation of its activity can be achieved through its interaction with phospholipids (PLs) and synthetic small molecules. We employed molecular dynamics (MD) simulations to understand more about the structural basis of LRH-1’s activity when bound to small molecule agonist RJW100 as well as the RJW100 derivative 65endo. We find that RJW100 and derivative 65endo can trigger allosteric communication in LRH-1 despite the RJW100 scaffold inducing motions that differ from those induced by PLs. We also provide supporting evidence that a key threonine residue and a water network may be important in RJW100’s ability to activate LRH-1. Finally, in a campaign to identify new LRH-1 lead compounds, virtual screening was performed against RJW100, 65endo, and a second RJW100 derivative, 8AC