Journal Article

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

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

2018

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Amino acids / Binding Sites / Cancer / Computer Simulation / Dose-Response Relationship, Drug / Drug Discovery - methods / Drug Evaluation, Preclinical / Esophageal cancer / Glioma / Head & neck cancer / Humans / Hydrogen bonds / Hypotheses / Large Neutral Amino Acid-Transporter 1 - chemistry / Large Neutral Amino Acid-Transporter 1 - metabolism / Ligands / Lung cancer / Molecular Docking Simulation / Molecular Dynamics Simulation / Molecular Structure / Protein Binding / Protein synthesis / Proteins / Structure-Activity Relationship / Tumors / Workflow