Computational insights on molecular interactions of acifran with GPR109A and GPR109B

Acifran is a well-known agonist of G-protein-coupled receptor protein, namely GPR109A. Acifran is primarily used in the treatment of dyslipidemia, myocardial infractions, and atherosclerosis in humans due to its lower vascular and metabolic side effects. However, experimental and computational studies on interaction sites of acifran with GPR proteins (GPR109A and GPR109B) are lacking. Our computational studies using docking and molecular dynamics simulation revealed that acifran binds distinctly to both GPR109A and GPR109B, but with lower affinity to the latter. The weak binding of acifran-GPR109B is mainly due to the presence of residues S91 and N94 in ECL1 and I178 amino acid in ECL2 region of GPR109B, whereas R111 and R251 residues in TMH3 and TMH6 are crucial for GPR109A-acifran complex stability. Additionally, molecular mechanics/Poisson-Boltzmann solvent accessible surface area (MM/PBSA) analysis revealed that both GPR109A- and GPR109B-acifran complexes are energetically stable with lower calculated binding free energy values for the latter.

Automated summary

This study investigated the interaction sites of acifran with G-protein-coupled receptor proteins, specifically GPR109A and GPR109B. Computational studies revealed that acifran binds differently to both receptors, with lower affinity to GPR109B. The weaker binding of acifran-GPR109B can be attributed to specific amino acid residues in the receptor's ECL1 and ECL2 regions. On the other hand, stability of the GPR109A-acifran complex relies on key residues in TMH3 and TMH6. Energy analysis showed that both GPR109A- and GPR109B-acifran complexes are energetically stable, with lower binding free energy values for the latter.