Free fatty acid receptors beyond fatty acids: A computational journey to explore peptides as possible binders of GPR120.

Free fatty acids receptors, with members among G protein-coupled receptors (GPCRs), are crucial for biological signaling, including the perception of the so called "fatty taste". In recent years, GPR120, a protein belonging to the GPCR family, drew attention as an interesting pharmacological target to cope with obesity, satiety and diabetes. Apart from long chain fatty acids, which are GPR120 natural agonists, other synthetic molecules were identified as agonists expanding the chemical space of GPR120's ligands. In this scenario, we unveiled peptides as possible GPR120 binders toward a better understanding of this multifaceted and relevant target. This study analyzed a virtual library collecting 531 441 low-polar hexapeptides, providing mechanistic insights on the GPR120 activation and further extending the possible chemical space of GPR120 agonists. The computational pipeline started with a narrow filtering of hexapeptides based on their chemical similarity with known GPR120 agonists. The best hits were tested through docking studies, molecular dynamics and umbrella sampling simulations, which pointed to G[I,L]FGGG as a promising GPR120 agonist sequence. The presence of both peptides in food-related proteins was thoroughly assessed, revealing they may occur in mushrooms, food-grade bacteria and rice. Simulations on the counterparts with D-amino acids were also performed. Umbrella sampling simulations described that GdIFGGG may have a better interaction compared to its all-L counterpart (-13 kCal/mol ΔG and -6 kCal/mol ΔG, respectively). Overall, we obtained a predictive model to better understand the underpinning mechanism of GPR120-hexapeptides interaction, hierarchizing novel potential agonist peptides for further analysis and describing promising food sources worth of further dedicated investigations.

A mechanistic investigation on kokumi-active γ-Glutamyl tripeptides - A computational study to understand molecular basis of their activity and to identify novel potential kokumi-tasting sequences.

Kokumi is an important taste perception whose chemical basis still needs clarifications and for which the development of high-throughput tools of analysis is desirable. The activation of Calcium-sensing receptor (CaSR) was described as the basis of kokumi perception allowing the use of molecular modelling to deepen its chemical rationale and related mechanisms. This study focused on γ-Glutamyl tripeptides, computationally providing mechanistic insights on their CaSR-activating properties and extended the comprehension of their structure-activity relationship. A library of 400 γ-Glutamyl tripeptides was also screened. γ-Glu-Pro-Ala and γ-Glu-Pro-Ser were identified for further dedicated investigations based on their promising CaSR-activating potential and their presence should be checked accordingly in food matrices to better profile the kokumi fingerprint. This work provided a meaningful tool for the top-down analysis of kokumi-active molecules that may support either the identification of kokumi molecules concealed in food or the rational design of kokumi-active molecules de novo.