Definition of an Uptake Pharmacophore of the Serotonin Transporter Through 3D-QSAR Analysis

Abstract

The serotonergic system plays a critical role in a wide variety of physiological and behavioral processes. Dysregulation of the tightly controlled extracellular concentration of serotonin (5-hydroxytryptamine, 5-HT) appears to be at the origin of a host of metabolic and psychiatric disorders. Since the plasma membrane 5-HT transporter (SERT) is the major protagonist in regulating extracellular 5-HT concentration, SERT is the target of most drugs interacting with the serotonergic system. Unfortunately, some of the drugs towards SERT (e.g. amphetamine derivatives) interfere with cell homeostasis leading to cell toxicity. Developing new SERT ligands devoid of any side-effect represents a major priority in the treatment of 5-HT-associated pathologies. Here, we report structure-activity relationships (SAR) and three-dimensional QSAR (3D-QSAR) studies of a library of 121 compounds including 5-HT analogs, harmanes, benzothiazoles, indanones, amphetamine derivatives and substrate-type 5-HT releasers, with the goal of identifying the structural determinants crucial for SERT uptake. In the absence of data about the bioactive form of 5-HT, conformational analysis of 5-HT was performed using quantum chemistry calculations. This led to three 5-HT stable conformers with anti, -gauche and +gauche side-chain conformation. These conformers, used as templates for superimposition with all the library compounds, enabled the design of a reliable 6-points pharmacophore representative of SERT uptake activity. Molecular dynamics (MD) simulations performed with compounds that are efficiently, moderately, poorly or not transported by SERT allowed to assess the validity of our pharmacophore. Altogether, our data provide for the first time a reliable pharmacophore of SERT uptake activity, which may help to the design of new drugs targeting SERT.

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

“…Hereby, the volume of the S1 pocket is reduced, so that only amino acids with no or small side chains such as Gly and Ala can be accommodated in the glycine transporters. In contrast, the equivalent positions in the S1 site in SERT, DAT, and NET contain amino acids with smaller-sized side chains in accordance with accommodation of larger substrates ( Figure 6) (Pratuangdejkul et al, 2005;Celik et al, 2008b).…”

Homology Modeling of the Serotonin Transporter: Insights into the Primary Escitalopram‐binding Site

“…Residues in the transporter have been studied by mutagenesis, and various pharmacophore models have been constructed for SERT ligands, including models for the substrate [9] and reuptake inhibitors. [10][11][12][13][14][15] Results from such studies provide direct and indirect structural insight into the possible interaction patterns between ligands and the transporter.…”

Molecular Dynamics Simulations of Na+/Cl−‐Dependent Neurotransmitter Transporters in a Membrane‐Aqueous System

“…At the present time, no X-ray structure is available for this target, but pharmacophore and homology modeling approaches have been used to gain insights into essential protein-ligand interaction patterns in three dimensions. [8][9][10][11][12][13][14] Various homology models have previously been constructed for the monoamine transporters. However, these have been based on the X-ray structures of 12TM transporters from the major facilitator superfamily (MFS) and from the NhaA antiporter family.…”

“…This docking pose gave rise to protein-ligand interactions as proposed in a 5-HT pharmacophore model. [8][9][10][11][12][13][14] In the obtained binding mode, 5-HT was in contact with several residues experimentally proven to be important for substrate binding, for example, D98, I172, and Y176 [51][52][53][54] , cf. Figure 1 a.…”