Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics

Area of Science:

• Biochemistry
• Pharmacology
• Structural Biology

Background:

• Free Fatty Acid Receptor 1 (FFAR1), also known as GPR40, is a G protein-coupled receptor (GPCR) targeted for type 2 diabetes mellitus (T2DM) treatment.
• FFAR1 activation by free fatty acids enhances glucose-dependent insulin secretion, but its activation mechanism is complex due to unique structural features and allosteric binding sites.

Purpose of the Study:

• To investigate the binding and unbinding mechanisms of FFAR1 agonists using computational methods.
• To elucidate the allosteric communication between the two identified binding sites within FFAR1.
• To provide insights for computer-aided drug design targeting FFAR1.

Main Methods:

• Utilized molecular dynamics (MD) and supervised molecular dynamics (SuMD) simulations.
• Analyzed the interaction of the partial agonist MK-8666 with FFAR1.
• Examined allosteric communications between FFAR1 binding sites.

Main Results:

• The extracellular loop 2 (ECL2) of FFAR1 was identified as the key region mediating MK-8666 binding.
• Simulations demonstrated reciprocal stabilization between FFAR1 agonists MK-8666 and AP8.
• The presence of AP8 was shown to influence the unbinding kinetics of MK-8666 from FFAR1.

Conclusions:

• FFAR1's unique structural properties and allosteric communication pathways are crucial for its activation mechanism.
• Understanding these mechanisms provides a foundation for developing novel T2DM therapeutics targeting FFAR1.
• Computational approaches like MD and SuMD are valuable tools for dissecting GPCR function and guiding drug discovery.