GPR120/free fatty acid receptor 4 (FFAR-4) agonists, antagonists, allosteric modulators: Computational drug design...

GPR120 (free fatty acid receptor 4, FFAR4) has recently emerged as promising therapeutic target with implications for therapies targeted at neurodegeneration, metabolic disorders, cancer, inflammation and cardiovascular diseases. The context dependent signaling and the tissue-specific expression of GPR120 has further complicated the drug development efforts. In this review, we comprehensively examined the current landscape of GPR120 modulation, integrating the GPR120 pharmacology with recent advances in the orthosteric and allosteric modulation, structure-based drug design and computational discovery strategies specifically targeted towards GPR120 receptors and downstream signaling. This review focuses on the functional significance of GPR120 isoforms, their site-specific expression and signal-bias and their role across obesity, type 2 diabetes, neurodegeneration, cancer, inflammation and cardiovascular pathologies. Orthosteric agonists, antagonists and allosteric modulators including endogenous, synthetic and computational derived modulators are systematically analyzed. Structure-based design strategies enabling optimization of the modulators, revealing critical mechanisms of binding, activation, sensitization and downstream signaling has been extensively covered, revealing the critical aromatic residue network (W198, W207, F115, F211, F303/F304) and indispensable role of R99 polar head groups recognition and interactions, conserved activation toggle switch W277, triad amino acids P5.50-I3.40-F6.44 triad, and ionic lock disruption (R136-D259) as a activation hallmarks. Inactive-active state stabilization via W277-N313 constraints informed antagonist development. Emerging allosteric modulation of GPR120 through natural partial agonists are comprehensively discussed. Finally, in this review we summarized comprehensively the computational methodologies spanning around homology modelling in pre- and post-cryo-EM era to native structure-guided approaches, multi-software docking, molecular dynamics simulations and virtual screening pipeline - including a large scale hexapeptide library screening yielding stereo-specific amino acid peptides with >100-fold potency. This review provides a roadmap for rational design of GPR120-targeted therapeutics that are pathway-selective and tissue-specific.