Pharmacophore modelling of stereoselective binding to the human organic cation transporter (hOCT1).
OBJECTIVE
The human organic cation transporter-1 (hOCT1) is a polyspecific transporter that plays a role in drug distribution, metabolism and excretion. Previous studies have demonstrated that hOCT1 binding can be stereoselective, but the mechanism for stereochemical recognition has not been described. The purpose of this study was to develop a pharmacophore model to describe stereoselective binding to hOCT1.


METHODS
A set of 22 compounds including 8 pairs of enantiomers and five pairs of diastereomers was used to develop a pharmacophore model. The pharmacophore modeling was carried out using Catalyst version 4.11 and HypoGen and was based upon the correlation of the structures and activities (K(i) values) of the compounds used in the study.


RESULTS
The resulting model contained a positive ion, hydrophobic and two hydrogen-bond acceptor interaction sites. The relative enantioselectivity of 8/8 enantiomeric pairs and diastereoselectivity of 5/5 diastereomers was described by mapping to a combination of at least 3 of the 4 functional feature sites of the model.


CONCLUSIONS
The pharmacophore model describes stereoselective interactions with hOCT1 at one of the binding sites on the molecule.
Moaddel
R
R
Gerontology Research Center, National institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Ravichandran
S
S
Bighi
F
F
Yamaguchi
R
R
Wainer
I W
IW
D001665:Binding Sites; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D027702:Organic Cation Transporter 1