Determination and modelling of stereoselective interactions of ligands with drug transporters: a key dimension in the understanding of drug disposition.
1. Stereochemistry is an important dimension in pharmacology and plays a role in every aspect of the pharmacological fate of chiral xenobiotics. This includes small molecule-drug transporter binding. 2. This paper reviews the reported stereoselectivities of substrate and inhibitor interactions with P-glycoprotein and the organic cation transporter obtained using standard functional and binding studies, as well as data obtained from online cellular membrane affinity chromatography studies. 3. The use of stereochemical data in quantitative structure-activity relationship (QSAR) and pharmacophore modelling is also addressed as is the effect of ignoring the fact that small molecule-drug transporter interactions take place in three-dimensional and asymmetric space.
Bhatia
P
P
Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA.
Kolinski
M
M
Moaddel
R
R
Jozwiak
K
K
Wainer
I W
IW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D015262:Xenobiotics / Q000737:chemistry* / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008024:Ligands; D015262:Xenobiotics