Lena Tagmose

Molecular dynamics simulations of Na+/Cl(-)-dependent neurotransmitter transporters in a membrane-aqueous system.

We have performed molecular dynamics simulations of a homology model of the human serotonin transporter (hSERT) in a membrane environment and in complex with either the natural substrate 5‐HT or the selective serotonin reuptake inhibitor escitalopram. We have also included a transporter homologue, the Aquifex aeolicus leucine transporter (LeuT), in our study to evaluate the applicability of a simple and computationally attractive membrane system. Fluctuations in LeuT extracted from simulations are in good agreement with crystallographic B factors. Furthermore, key interactions identified in the X‐ray structure of LeuT are maintained throughout the simulations indicating that our simple membrane system is suitable for studying the transmembrane protein hSERT in complex with 5‐HT or escitalopram. For these transporter complexes, only relatively small fluctuations are observed in the ligand‐binding cleft. Specific interactions responsible for ligand recognition, are identified in the hSERT–5HT and hSERT–escitalopram complexes. Our findings are in good agreement with predictions from mutagenesis studies.

Homology modeling of the serotonin transporter: insights into the primary escitalopram-binding site.

The serotonin transporter (SERT) is one of the neurotransmitter transporters that plays a critical role in the regulation of endogenous amine concentrations and therefore is an important target for therapeutic agents affecting the central nervous system. The recently published, high resolution X‐ray structure of the closely related amino acid transporter, Aquifex aeolicus leucine transporter (LeuT), provides an opportunity to develop a three‐dimensional model of the structure of SERT. We present herein a homology model of SERT using LeuT as the template and containing escitalopram as a bound ligand. Our model explains selectivities known from mutational studies and varying ligand data, which are discussed and illustrated in the paper.

The identification of AF38469: An orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin.

The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.

Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex

The identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex are reported.

Chapter Four - Selective Inhibitors of PDE2, PDE9, and PDE10: Modulators of Activity of the Central Nervous System

Abstract Although superficially similar, the currently most advanced inhibitors of PDE2, PDE9, and PDE10 for central nervous system disorders differ in a number of ways. PDE9 appears to be very restrictive in its binding motif requirements: in essence only one chemotype, emulating the GMP bidentate-binding motif, covers the known PDE9 chemical space. A much larger diversity of compounds is described for inhibitors of PDE2: it appears as if the less stringent requirements for binding to the invariant glutamine (Gln) in combination with the induced hydrophobic (selectivity) pocket allow a much broader variety of inhibitor chemotypes. PDE10 also has less stringent structural requirements and accepts more structurally diverse inhibitors compared to PDE9. The PDE10-unique Q2 pocket provides an additional opportunity for diversity in compounds targeting this enzyme. In special cases, high affinities can be obtained without even interacting with the central Gln.