3-D-QSAR and docking studies on the neuronal choline transporter |
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Authors: | Werner J Geldenhuys David D Allen Paul R Lockman |
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Institution: | 1. Department of Pharmaceutical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA;2. Department of Pharmaceutical Sciences, Texas Tech Health Sciences Center, School of Pharmacy, Amarillo, TX 79106, USA |
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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 q2 of 0.5, and a non-cross validated r2 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. |
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