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

Area of Science:

• Pharmacology
• Computational Chemistry
• Molecular Biology

Background:

• Bexarotene is an FDA-approved retinoid X-receptor (RXR) agonist used for cutaneous T-cell lymphoma.
• Investigational uses for bexarotene include other cancers and Alzheimer's disease.
• Serious side effects associated with bexarotene may be mitigated through molecular modifications.

Purpose of the Study:

• To rationalize existing RXR agonists.
• To identify potential sites for chemical substitutions in bexarotene.
• To guide the design of novel, higher-affinity bexarotene-like ligands.

Main Methods:

• Molecular flooding simulations of the RXR ligand-binding domain with diverse drug-like molecules.
• Molecular dynamics simulations of bexarotene-like ligands bound to the RXR ligand-binding domain.
• Analysis of ligand-receptor interactions, positional fluctuations, hydrogen bonding, and solvation.

Main Results:

• Two key regions for ligand modification were identified: a hydrophobic area near the bridgehead and another near the fused ring.
• The fused ring exhibited greater positional fluctuation than the phenyl ring, suggesting it as a target for affinity enhancement.
• Significant differences in ligand interactions were observed between RXRα and RXRβ subtypes.

Conclusions:

• The fused ring of bexarotene is a promising target for designing higher-affinity ligands, while the phenyl ring appears optimized.
• Exploiting observed differences between RXRα and RXRβ could lead to the development of subspecies-specific ligands.
• Computational simulations provide a rational basis for modifying bexarotene to improve its therapeutic profile and reduce side effects.