Molecular modeling studies on the active binding site of the blood-brain barrier choline transporter.

The blood-brain barrier choline transporter may have utility as a drug delivery vector to the central nervous system. Surprisingly, this transporter has as yet not been cloned and expressed. We therefore initiated a 3D-QSAR study to develop predictive models for compound binding and identify structural features important for binding to this transporter. In vivo experimental data were obtained from in situ rat brain perfusion studies. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods were used to build the models. The best cross-validated CoMFA q(2) was found to be 0.47 and the non-cross-validated r(2) was 0.95. CoMSIA hydrophobic cross-validated q(2) was 0.37 and the non-cross-validated r(2) was 0.85. These models rendered a useful approximation for binding requirements in the BBB-choline transporter and, until such time as the cloned transporter becomes available, may have significant utility in developing a predictive model for the rational design of drugs targeted to the brain.