Bioorganic & Medicinal Chemistry Letters 2010-08-15

3-D-QSAR and docking studies on the neuronal choline transporter.

Werner J Geldenhuys, David D Allen, Paul R Lockman

Index: Bioorg. Med. Chem. Lett. 20 , 4870-7, (2010)

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Abstract

The high affinity neuronal choline transporter (CHT1) is responsible for the uptake of choline into the pre-synaptic terminal of cholinergic neurons. Considering our past experience with modeling the blood-brain barrier choline transporter (BBBCHT) as drug delivery vector to the CNS, we investigated the 3-D-quantitative structure-activity relationship of the neuronal choline transporter. Comparative molecular field analysis (CoMFA) and comparative similarity index analysis (CoMSIA) yielded cross-validated models with a q(2) of 0.5, and a non-cross validated r(2) of 0.8. The electrostatic results of the 3-D-QSAR models are corroborated with a docking study into the bacterial choline transporter. Using this electrostatic map, we propose a putative binding site in a homology model of the CHT1. Knowledge gained from this study is useful to better understand the CHT1 as well as can be used in medicinal chemistry programs targeting this transporter.2010 Elsevier Ltd. All rights reserved.