Structure-activity Relationship Study of Compounds Binding to Large Amino Acid Transporter 1 (LAT1) Based on Pharmacophore Modeling and in Situ Rat Brain Perfusion

Large neutral amino acid transporter 1 (LAT1) is predominantly expressed at the blood-brain barrier and it has a major role in transporting neutral amino acids into the brain. LAT1 has the potential to function as a drug carrier for improved drug brain delivery which makes it an intriguing target protein for central nervous system disorders, e.g., Alzheimer's disease, Parkinson's disease and brain tumors. In this study, a 3D pharmacophore was generated for a set of LAT1 substrates whose binding affinities were studied using competitive inhibition of the brain uptake of [¹⁴C]-L-leucine with an in situ rat brain perfusion method. The pharmacophore highlights the most important molecular features shared by efficient LAT1-binding compounds and elucidates their 3D-arrangement in detail. This clarifies the structure-activity relationships of LAT1 substrates and provides insights for making a binding hypothesis. The results can be further applied in the design of novel efficient LAT1 substrates.