Homology Modeling and Ligand Optimization for the Human Amino Acid Exchanger Lat-1 (SLC7A5)

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LAT-1 (SLC7A5) is a sodium-independent exchanger mainly located in the blood brain barrier (BBB) where it mediates the transport of large neutral amino acids, thyroid hormones and prescription drugs. LAT-1 is also upregulated in a variety of cancer types (e.g., prostate cancer), to provide amino acids that are used as nutrients and signaling molecules for growth. Thus, LAT-1 is an emerging drug target for substrates that can serve as prodrugs with optimal BBB or tumor permeability, or inhibitors that starve cancer cells. Here, we use computational modeling using homology modeling and ligand docking, followed by experimental testing using synthetic chemistry and cellular uptake measurements, to develop homology models for LAT-1 and identify novel chemical tools for this transporter. We refine a homology model of LAT-1 based on the arginine/agmatine transporter AdiC from E. Coli as modeling template and conduct SAR studies on amino acid derivatives to design compounds with optimal Km/Vmax balance. Particularly, initial LAT-1 models and binding evaluation of putative compounds guided the synthesis of distinct compounds, including tyrosine and phenylalanine derivatives, carboxylic acid bioisosteres, and other unique scaffolds. These compounds were tested experimentally by your collaborators using cis-inhibition and trans-stimulation assays. For example, we identified hydroxamic acids derivatives as LAT-1 substrates for the first time. Furthermore, iterative evaluation of these compounds by computational methods and experimental testing permitted to progressively refine our LAT-1 models, reaveling previously unknown druggable pockets on its surface. Our results improve our understanding of how inhibition and transport specificity is determined in LAT-1, as well as provide novel chemical probes to further characterize the role of this transporter in cancer and neurological disorders.