Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods

Natesh Singh, Mariafrancesca Scalise, Michele Galluccio, Marcus Wieder, Thomas Seidel, Thierry Langer, Cesare Indiveri, Gerhard F Ecker

The large neutral amino acid transporter 1 (LAT1) is a promising anticancer target that is required for the cellular uptake of essential amino acids that serve as building blocks for cancer growth and proliferation. Here, we report a structure-based approach to identify chemically diverse and potent inhibitors of LAT1. First, a homology model of LAT1 that is based on the atomic structures of the prokaryotic homologs was constructed. Molecular docking of nitrogen mustards (NMs) with a wide range of affinity allowed for deriving a common binding mode that could explain the structure-activity relationship pattern in NMs. Subsequently, validated binding hypotheses were subjected to molecular dynamics simulation, which allowed for extracting a set of dynamic pharmacophores. Finally, a library of ~1.1 million molecules was virtually screened against these pharmacophores, followed by docking. Biological testing of the 30 top-ranked hits revealed 13 actives, with the best compound showing an IC50 value in the sub-μM range.

Department of Pharmaceutical Chemistry
External organisation(s)
Università della Calabria
International Journal of Molecular Sciences
Publication date
Peer reviewed
Austrian Fields of Science 2012
Pharmaceutical chemistry
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