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Research Themes Drug discovery

Drug Discovery: Modeling NET Interactions

SBKB [doi:10.1038/sbkb.2012.164]
Featured Article - October 2013
Short description: A structural model of the norepinephrine transporter is used in a virtual ligand screen to identify new drug interactions.

Predicted NET binding pocket and norepinephrine-binding mode. NET structure is drawn as white ribbons with key residues in sticks; norepinephrine is drawn in orange. Figure courtesy of Avner Schlessinger.

Sodium:neurotransmitter symporters (solute carriers 6, SLC6) form a family of ion-dependent transporter proteins that regulate a variety of biological activities through the uptake of neurotransmitters, osmolytes and amino acids into the cell. The norepinephrine transporter (NET) is responsible for the recycling of the neurotransmitter norepinephrine from the synaptic space into presynaptic neurons. NET mutations are associated with several behavioral disorders. NET is the target of drugs treating depression, anxiety and attention-deficit hyperactivity disorder, and may also mediate side effects from other prescription drugs. Many of these drugs are actually inhibitors of NET, preventing the reuptake of norepinephrine.

Schlessinger, Sali and colleagues (PSI CSMP and EFI) have employed a structure-based screening strategy to examine prescription drugs that may bind to NET. The authors generated a comparative model of NET based on the structure of the bacterial homolog LeuT (PDB 2A65), a leucine transporter from Aquifex aeolicus, and then validated the model by docking known NET ligands within the binding pocket. The modeled binding pocket is small and lined with several hydrophobic residues; additional key polar interactions were predicted from the docked NET-ligand complexes.

Next, a filtered set from the library of known drugs in the Kyoto Encyclopedia of Genes and Genomes was computationally screened against the NET model. Encouragingly, several known NET binders ranked highly within the screen. The authors manually analyzed the 200 highest-ranking hits and selected 18 novel drugs for experimental testing of the inhibition of [3H]norepinephrine uptake by NET in human embryonic kidney cells. These 18 were parsed into a “high-confidence” group, having a predicted binding mode nearly identical to norepinephrine, and a second “medium-confidence” group, having a dissimilar predicted binding mode and forming only one key polar interaction within the binding pocket. All members of the high-confidence group—which include a monoamine oxidase inhibitor, a nasal decongestant, an antidepressant and two adrenergic agents— showed significant levels of inhibition, as did several drugs in the medium-confidence group. In particular, two medium-confidence hits, an antidiabetic drug and a nasal decongestant, were shown to be potent inhibitors of NET activity.

Pharmacologically, the findings suggest that the characterized efficacy of some neuroactive drugs may be due to their ability to inhibit NET in addition to their intended target. Further, drugs used to treat conditions unrelated to NET activity (for example, diabetes) may produce side effects caused by NET inhibition. Finally, the modeling and docking methodology may be a promising approach to characterize unknown drug interactions with other membrane receptors and transporters.

Michelle Montoya

References

  1. A. Schlessinger et al. Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET.
    Proc Natl Acad Sci U S A. 108, 15810-15815 (2011). doi:10.1073/pnas.1106030108

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