Molecular dynamics simulations and molecular flooding studies of the retinoid X-receptor ligand binding domain

Bexarotene is an FDA approved retinoid X-receptor (RXR) agonist for the treatment of cutaneous T-cell lymphoma, and its use in other cancers and Alzheimer’s disease is being investigated. The drug causes serious side effects, which might be reduced by chemical modifications of the molecule. To rationalize known agonists and to help identify sites for potential substitutions we present molecular simulations in which the RXR ligand-binding domain was flooded with a large number of drug-like molecules, and molecular dynamics simulations of a series of bexarotene-like ligands bound to the RXR ligand-binding domain. Based on the flooding simulations, two regions of interest for ligand modifications were identified: a hydrophobic area near the bridgehead and another near the fused ring. In addition, positional fluctuations of the phenyl ring were generally smaller than fluctuations of the fused ring of the ligands. Together, these observations suggest that the fused ring might be a good target for the design of higher affinity bexarotene-like ligands, while the phenyl ring is already optimized. In addition, notable differences in ligand position and interactions between the RXRα and RXRβ were observed, as well as differences in hydrogen bonding and solvation, which might be exploited in the development of subspecies-specific ligands.