Liver-Type Fatty Acid Binding Protein (FABP1) Has Exceptional Affinity for Minor Cannabinoids

Fatty acid binding protein 1 (FABP1) is a lipid transporter primarily expressed in the liver where it helps move fatty acids between lipid membranes. Inhibition of FABP1 has potential therapeutic implications for nonalcoholic fatty liver disease, metabolic syndrome & obesity, diabetes, and inflammatory & cardiovascular diseases. Curiously, FABP1 is known to bind to both endocannabinoids (ECs) and the major phytocannabinoids (PCs) with moderately high affinities. We have developed an in-silico model of the protein and validated it against experimental data. We then employed the model to predict the binding mode and affinities of minor cannabinoids (MCs) to FABP1. Our study predicts that the top ranked MCs 5-acetyl-4-hydroxy-CBG and CBGA bind stronger than fatty acids (FAs), ECs or PCs, and participate in the key interactions used to stabilize FABP1-FA complexes. This makes them promising starting points for the development of new therapeutics. The implications this has on considering the minor cannabinoids as low entropy isosteres of the fatty acids is also discussed.