title: Different Binding Modes of Small and Large Binders of GAT1.
abstract: Well-known inhibitors of the γ-aminobutyric acid (GABA) transporter GAT1 share a common scaffold of a small cyclic amino acid linked by an alkyl chain to a moiety with two aromatic rings. Tiagabine, the only FDA-approved GAT1 inhibitor, is a typical example. Some small amino acids such as (R)-nipecotic acid are medium-to-strong binders of GAT1, but similar compounds, such as proline, are very weak binders. When substituted with 4,4-diphenylbut-3-en-1-yl (DPB) or 4,4-bis(3-methylthiophen-2-yl)but-3-en-1-yl (BTB) groups, the resulting compounds have similar pKi and pIC50 values, even though the pure amino acids have very different values. To investigate if small amino acids and their substituted counterparts share a similar binding mode, we synthesized butyl-, DPB-, and BTB-substituted derivatives of small amino acids. Supported by the results of docking studies, we propose different binding modes not only for unsubstituted und substituted, but also for strong- and weak-binding amino acids. These data lead to the conclusion that following a fragment-based approach, not pure but N-butyl-substituted amino acids should be used as starting points, giving a better estimate of the activity when a BTB or DPB substituent is added.
authors.affiliation: Department for Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wein
authors.affiliation: Galliera Hospital, Mura delle Cappuccine 14, 16128, Genova, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Petrera
authors.affiliation: Department for Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377, Munich, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Allmendinger
authors.affiliation: Department for Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.affiliation: Department for Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377, Munich, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Pabel
authors.affiliation: Department for Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377, Munich, Germany. klaus.wanner@cup.uni-muenchen.de.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009557:Nipecotic Acids / Q000378:metabolism; D011485:Protein Binding
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D009557:Nipecotic Acids; C030278:nipecotic acid
keywords: GABA transporter; GAT1; docking; homology modeling; tiagabine