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

  • Int J Mol Sci. 2018 Dec 21;20(1):27. doi: 10.3390/ijms20010027.
Natesh Singh  1 ,  Mariafrancesca Scalise  2 ,  Michele Galluccio  3 ,  Marcus Wieder  4 ,  Thomas Seidel  5 ,  Thierry Langer  6 ,  Cesare Indiveri  7 ,  Gerhard F Ecker  8
Affiliations
  • 1. Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Wien, Austria. [email protected].
  • 2. Department DiBEST, Unit of Biochemistry & Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, 87036 Arcavacata di Rende, Italy. [email protected].
  • 3. Department DiBEST, Unit of Biochemistry & Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, 87036 Arcavacata di Rende, Italy. [email protected].
  • 4. Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Wien, Austria. [email protected].
  • 5. Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Wien, Austria. [email protected].
  • 6. Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Wien, Austria. [email protected].
  • 7. Department DiBEST, Unit of Biochemistry & Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, 87036 Arcavacata di Rende, Italy. [email protected].
  • 8. Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Wien, Austria. [email protected].
PMID: 30577601 DOI: 10.3390/ijms20010027
Abstract

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.

Keywords
LAT1; amino acid transporter; cancer; inhibitor; proteoliposomes; virtual screening.
Products