Structural determinants of sphingosine-1-phosphate receptor selectivity

Area of Science:

• Pharmacology
• Computational Chemistry
• Neuroscience

Background:

• Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator, was the first drug for multiple sclerosis, but its unselective action across S1PR subtypes causes adverse effects.
• Agonism at S1PR1 mediates therapeutic immune modulation, while S1PR3 agonism is linked to cardiac issues, driving the need for selective compounds.
• Second-generation S1PR modulators like siponimod and ozanimod are selective for S1PR1 and S1PR5, aiming to mitigate side effects.

Purpose of the Study:

• To elucidate S1PR subtype-specific binding site characteristics using molecular dynamics and pharmacophore modeling.
• To visualize subtle differences in receptor-ligand interactions for developing selective S1PR modulators.
• To understand the mechanistic basis for the selectivity profiles of approved drugs and tool compounds.

Main Methods:

• Combined molecular dynamics (MD) simulations with three-dimensional pharmacophores (dynophores).
• Analyzed binding site characteristics and receptor-ligand interactions across S1PR subtypes.
• Investigated the binding dynamics of fingolimod-1-phosphate (F1P) and sphingosine-1-phosphate.

Main Results:

• Identified distinct binding mode dynamics for F1P and sphingosine-1-phosphate within the S1PR orthosteric pocket.
• Visualized subtle differences in ligand interactions across S1PR subtypes.
• Provided insights into the structural basis for the selectivity of drugs like ozanimod and siponimod.

Conclusions:

• The study offers a method to characterize S1PR subtype-specific binding, aiding the design of selective ligands.
• Understanding binding dynamics is crucial for developing safer and more effective S1PR modulators.
• The findings contribute to the mechanistic understanding of existing S1PR drugs and guide future drug discovery efforts.