Three-dimensional models of neurotransmitter transporters and their interactions with cocaine and S-citalopram.
Drugs that act on the human serotonin transporter (hSERT), human dopamine transporter (hDAT) and human noradrenaline transporter (hNET) are important in antidepressant treatment and well known in drug abuse. The investigation of their molecular mechanisms of action is very useful for designing new ligands with a therapeutic potential. The detailed three-dimensional molecular structure of any monoamine transporter is not known, but the three-dimensional electron density projection map of Escherichia coli Na+/H+ antiporter (NhaA) has provided structural basis for constructing models of such transporters using molecular modelling techniques. Three-dimensional models of these drug targets give insight into their structure, mechanisms and drug interactions. In these molecular modelling studies, an Escherichia coli NhaA model was first constructed based on its three-dimensional electron density projection map and experimental studies on NhaA and the Escherichia coli lactose permease symporter (Lac permease). Then three-dimensional models of the neurotransmitter transporters hDAT, hSERT and hNET were constructed based on the NhaA model and studies of ligand binding to mutated dopamine transporter (DAT) and serotonin transporter (SERT). The structural properties of these neurotransmitter transporter models have been examined, and their interactions with cocaine and S-citalopram have been investigated.
Ravna
Aina Westrheim
AW
Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway. aina@fagmed.uit.no