Identification of selective norbornane-type aspartate analogue inhibitors of the glutamate transporter 1 (GLT-1) from the chemical universe generated database (GDB)

J Med Chem. 2010 Oct 14;53(19):7236-50. doi: 10.1021/jm100959g.

Abstract

A variety of conformationally constrained aspartate and glutamate analogues inhibit the glutamate transporter 1 (GLT-1, also known as EAAT2). To expand the search for such analogues, a virtual library of aliphatic aspartate and glutamate analogues was generated starting from the chemical universe database GDB-11, which contains 26.4 million possible molecules up to 11 atoms of C, N, O, F, resulting in 101026 aspartate analogues and 151285 glutamate analogues. Virtual screening was realized by high-throughput docking to the glutamate binding site of the glutamate transporter homologue from Pyrococcus horikoshii (PDB code: 1XFH ) using Autodock. Norbornane-type aspartate analogues were selected from the top-scoring virtual hits and synthesized. Testing and optimization led to the identification of (1R*,2R*,3S*,4R*,6R*)-2-amino-6-phenethyl-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid as a new inhibitor of GLT-1 with IC(50) = 1.4 μM against GLT-1 and no inhibition of the related transporter EAAC1. The systematic diversification of known ligands by enumeration with help of GDB followed by virtual screening, synthesis, and testing as exemplified here provides a general strategy for drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Cyclic / chemical synthesis*
  • Amino Acids, Cyclic / chemistry
  • Amino Acids, Cyclic / pharmacology
  • Animals
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / chemical synthesis*
  • Aspartic Acid / chemistry
  • Aspartic Acid / pharmacology
  • Bacterial Proteins / chemistry
  • Databases, Factual*
  • Excitatory Amino Acid Transporter 2 / antagonists & inhibitors*
  • Excitatory Amino Acid Transporter 3 / antagonists & inhibitors
  • Female
  • Glutamates / chemical synthesis*
  • Glutamates / chemistry
  • Glutamates / pharmacology
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Norbornanes / chemical synthesis*
  • Norbornanes / chemistry
  • Norbornanes / pharmacology
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Protein Binding
  • Pyrococcus horikoshii
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xenopus laevis

Substances

  • 2-amino-6-phenethylbicyclo(2.2.1)heptane-2,3-dicarboxylic acid
  • Amino Acids, Cyclic
  • Bacterial Proteins
  • Excitatory Amino Acid Transporter 2
  • Excitatory Amino Acid Transporter 3
  • Glutamates
  • Ligands
  • Norbornanes
  • Aspartic Acid