REV-ERBA is a nuclear hormone receptor that holds therapeutic potential in several diseases. SR8278 is the only REV-ERBα antagonist known for 10 years and was used extensively as a chemical probe to explore its role in REV-ERB pharmacology. The absence of Xray structure of REV-ERBα bound with synthetic ligands further hindered the discovery of novel modulators against this drug target. We have performed gaussian accelerated molecular dynamics (GaMD) simulations to sample the binding pathway of the SR8278 ligand and associated conformational changes in REV-ERBα. The simulations revealed a previously unobserved open-pocket state that, unlike the unliganded state, allows ligand ready access and binding to the orthosteric binding site. This state is reached after a tryptophan (Trp436) rotameric switch coupled with helix3-helix6 distance change. Several ligand binding and dissociation events to the orthosteric pocket were observed with distinct low-energy conformational states recognized, indicating convergence and proper sampling in the simulations. This study provides important insights into the REV-ERBα functional mechanism. The newly identified open-pocket state open further opportunities for small molecule drug discovery using structure-based approaches.

How does the antagonist SR8278 bind to REV-ERBα?

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.