Computational insights on molecular interactions of acifran with GPR109A and GPR109B

Abstract

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. Energy-minimized structures of GPR109A-acifran and GPR109B-acifran complex.

Keywords: Acifran; G-Protein-Coupled Receptor; Molecular dynamics simulations; Molecular mechanics/Poisson-Boltzmann surface area.