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Structure–activity relationship study of compounds binding to large amino acid transporter 1 (LAT1) based on pharmacophore modeling and in situ rat brain perfusion

2012; Elsevier BV; Volume: 48; Issue: 3 Linguagem: Inglês

10.1016/j.ejps.2012.11.014

1879-0720

Henna Ylikangas, Lauri Peura, Kalle Malmioja, Jukka Leppänen, Krista Laine, Antti Poso, Maija Lahtela‐Kakkonen, Jarkko Rautio,

Molecular Sensors and Ion Detection

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.