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

Luethi, Erika; Nguyen, Kong T; Bürzle, Marc; Blum, Lorenz C; Suzuki, Yoshiro; Hediger, Matthias; Reymond, Jean-Louis (2010). Identification of selective norbornane-type aspartate analogue inhibitors of the glutamate transporter 1 (GLT-1) from the chemical universe generated database (GDB). Journal of medicinal chemistry, 53(19), pp. 7236-50. Easton, Pa.: American Chemical Society 10.1021/jm100959g

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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 ?M 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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine 08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)
UniBE Contributor:	Bürzle, Marc, Hediger, Matthias, Reymond, Jean-Louis
ISSN:	0022-2623
Publisher:	American Chemical Society
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:12
Last Modified:	05 Dec 2022 14:01
Publisher DOI:	10.1021/jm100959g
PubMed ID:	20812729
Web of Science ID:	000282544800038
URI:	https://boris.unibe.ch/id/eprint/2424 (FactScience: 204919)