Computational insights on molecular interaction of acifran with GPR109A and GPR109B

Authors: ADEPU, KIRAN KUMAR - Arkansas Children'S Nutrition Research Center (ACNC); KACHHAP, SANGITHA - Polish Academy Of Sciences; BHANDARI, DIPENDRA - Arkansas Children'S Nutrition Research Center (ACNC); ANISHKIN, ANDRIY - University Of Maryland; CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Journal of Molecular Modeling
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/16/2022
Publication Date: 7/28/2022
Citation: Adepu, K., Kachhap, S., Bhandari, D., Anishkin, A., Chintapalli, S.V. 2022. Computational insights on molecular interaction of acifran with GPR109A and GPR109B. Journal of Molecular Modeling. https://doi.org/10.1007/s00894-022-05233-5.
DOI: https://doi.org/10.1007/s00894-022-05233-5

Interpretive Summary: Vitamin B12 (also known as Niacin) binds to membrane protein, GPR109A and regulates various biological processes like immune system, cell density signaling, behavioral and mood regulation, homeostasis modulation, visual sense, sense of smell and autonomous nervous system transmission. However, high doses of niacin intake are associated with various side effects like subcutaneous flushing and fatty acid rebound. Other hypolipidemic agents, like Acifran, is preferred over niacin because of its advantages over the later. Acifran also decreases hydrolysis of triglycerides and fatty acids. This might be due to its binding and activation of both GPR109A and GPR109B, which is not fully understood yet. Here, we have studied detailed structural and molecular insights on interaction between acifran with GPR109A and GPR109B, which could reveal novel targets towards development of potential therapeutic agents.

Technical 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) is 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 later. 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 complex(es) are energetically stable with lower calculated binding free energy values for the later.