MOLECULAR DOCKING AND PHARMACOKINETIC PROFILING OF SHORT-CHAIN FATTY ACIDS TARGETING G PROTEIN-COUPLED RECEPTORS INVOLVED IN NEUROINFLAMMATION

Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are key microbial metabolites involved in immune regulation and gut-brain axis communication. Evidence suggests that SCFA effects are mediated through specific G protein-coupled receptors (GPRs) expressed by immune and glial cells. Among these, GPR41 and GPR109A are particularly implicated in microglial activation and neuroinflammatory signaling. However, the molecular mechanisms of SCFA-GPR interactions, as well as their pharmacokinetic and toxicological properties, remain poorly characterized.

To address this, an integrated in silico approach was employed. Molecular docking analyses were performed using AutoDock Tools to evaluate binding affinities (ΔG, kcal/mol) and identify key interaction residues between SCFAs and the selected receptors. Protein and ligand preparation, visualization, and interaction analysis were conducted using BIOVIA Discovery Studio Visualizer. Pharmacokinetic properties, including gastrointestinal absorption, blood-brain barrier permeability, and drug-likeness, were predicted using SwissADME, while toxicity profiles were assessed in silico.

Docking results revealed a hierarchy of binding affinities, with butyrate exhibiting the strongest interactions with GPR41 (ΔG = -5.1 kcal/mol) and GPR109A (ΔG = -4.0 kcal/mol), followed by propionate (-4.6 and -3.6 kcal/mol) and acetate (-3.9 and -3.0 kcal/mol). Pharmacokinetic predictions indicated favorable absorption and predicted BBB permeability for butyrate and propionate.

Overall, these findings provide molecular-level insights into SCFA-GPR interactions and support the potential role of SCFAs, especially butyrate, in modulating neuroinflammatory pathways via microglial receptors, highlighting their relevance for neurodevelopmental disorders.