Structure and localisation of drug binding sites on neurotransmitter transporters

• Published in: Journal of molecular modeling Vol. 15; no. 10; pp. 1155 - 1164
• Main Authors: Ravna, Aina W., Sylte, Ingebrigt, Dahl, Svein G.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.10.2009
• Subjects: Amino Acid Sequence; Binding Sites; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Dopamine Plasma Membrane Transport Proteins - metabolism; Humans; Models, Molecular; Molecular Medicine; Molecular Structure; Neurotransmitter Transport Proteins - metabolism; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Original Paper; Protein Binding; Psychotropic Drugs - pharmacokinetics; Serotonin Plasma Membrane Transport Proteins - metabolism; Theoretical and Computational Chemistry; Neurotransmitter; Binding site; Noradrenalin; Dopamine; Serotonin; Transporter protein
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-009-0478-1

The dopamine (DAT), serotontin (SERT) and noradrenalin (NET) transporters are molecular targets for different classes of psychotropic drugs. The crystal structure of Aquifex aeolicus LeuT Aa was used as a template for molecular modeling of DAT, SERT and NET, and two putative drug binding sites (pocket 1 and 2) in each transporter were identified. Cocaine was docked into binding pocket 1 of DAT, corresponding to the leucine binding site in LeuT Aa , which involved transmembrane helices (TMHs) 1, 3, 6 and 8. Clomipramine was docked into binding pocket 2 of DAT, involving TMHs 1, 3, 6, 10 and 11, and extracellular loops 4 and 6, corresponding to the clomipramine binding site in a crystal structure of a LeuT Aa –clomipramine complex. The structures of the proposed cocaine- and tricyclic antidepressant-binding sites may be of particular interest for the design of novel DAT interacting ligands.