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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-108540
    ≥98.0%, LAT1 Inhibitor