Deciphering the Structural Determinants Critical in Attaining the FXR Partial Agonism.

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Farnesoid X receptor (FXR) is a validated target for non-alcoholic steatohepatitis (NASH).
• Full agonism of FXR presents clinical challenges, making partial agonism (PA) a promising therapeutic strategy.
• Designing selective PA is complex due to shared binding sites and dynamic interactions within FXR.

Purpose of the Study:

• To identify structural and conformational determinants differentiating FXR partial agonists from full agonists.
• To elucidate the mechanism by which PA modulates FXR's structural dynamics at the residue level.
• To provide insights for structure-based drug discovery of FXR PA therapeutics.

Main Methods:

• Utilized approximately 4.5 microseconds of molecular dynamics (MD) simulations.
• Employed residue-wise communication network analysis to map molecular interactions.
• Performed thermodynamic profiling to identify key residues involved in PA binding.

Main Results:

• Identified specific flexible regions with PA that are rigid with full agonists.
• Network analysis revealed significant changes in crucial FXR regions (helix H10/H11, loop L:H11/H12) upon PA binding.
• Methionine residues (M328, M365, M450) and other specific residues (I357, Y361, L465, F308, Q316, K321) were implicated in PA recruitment and interaction.

Conclusions:

• This research provides novel structural and mechanistic understanding of FXR partial agonism.
• The findings are critical for the rational design of FXR-targeted drugs for NASH and other conditions.
• The identified residue-level interactions offer a roadmap for developing selective partial agonists.