Distinct REV-ERBα Conformational State Predicted by GaMD Simulations Leads to the Structure-Based Discovery of Novel REV-ERBα Antagonist

REV-ERB is a nuclear hormone receptor that plays important role in the regulation of many physiological processes such as circadian clock regulation, inflammation, and metabolism. Despite its importance, few chemical tools are available to study this receptor. In addition, there is no available X-ray crystal structures of REV-ERB bound with synthetic ligands, hampering the development of targeted therapeutics. SR8278 is the only identified synthetic antagonist of REV-ERB. We have performed Gaussian accelerated molecular dynamics (GaMD) simulations to sample the binding pathway of SR8278 and associated conformational changes to REV-ERB. The simulations revealed a novel and more energetically favorable conformational state than the starting conformation. The new conformation allows ligand binding to the orthosteric binding site in a specific orientation. This state is reached after a tryptophan (Trp436) rotameric switch coupled with H3-H6 distance change. We used the newly identified GaMD conformational state in structure-based virtual screening of one million compounds library which led to the identification of novel REV-ERB antagonist. This study is the first that demonstrates a synthetic ligand binding pathway to REV-ERB, which provided important insights into the REV-ERB functional mechanism and lead to the discovery of novel REV-ERB antagonists. This study further emphasizes the power of computational chemistry methods in advancing drug discovery research.