Structural determinants for transport across the intestinal bile acid transporter using C-24 bile acid conjugates

Mol Pharm. 2010 Dec 6;7(6):2240-54. doi: 10.1021/mp100233v. Epub 2010 Nov 1.


The human apical sodium dependent bile acid transporter (hASBT) reabsorbs gram quantities of bile acid daily and is a potential prodrug target to increase oral drug absorption. In the absence of a high resolution hASBT crystal structure, 3D-QSAR modeling may prove beneficial in designing prodrug targets to hASBT. The objective was to derive a conformationally sampled pharmacophore 3D-QSAR (CSP-SAR) model for the uptake of bile acid conjugates by hASBT. A series of bile acid conjugates of glutamyl chenodeoxycholate were evaluated in terms of K(m) and normalized V(max) (normV(max)) using hASBT-MDCK cells. All monoanionic conjugates were potent substrates. Dianions, cations and zwitterions, which bound with a high affinity, were not substrates. CSP-SAR models were derived using structural and physicochemical descriptors, and evaluated via cross validation. The best CSP-SAR model for K(m) included two structural and two physiochemical descriptors, where substrate hydrophobicity enhanced affinity. A best CSP-SAR model for K(m)/normV(max) employed one structural and three physicochemical descriptors, also indicating hydrophobicity enhanced efficiency. Overall, the bile acid C-24 region accommodated a range of substituted anilines, provided a single negative charge was present near C-24. In comparing uptake findings to prior inhibition results, increased hydrophobicity enhanced activity, with dianions and zwitterions hindering activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Chenodeoxycholic Acid / analogs & derivatives
  • Chenodeoxycholic Acid / chemistry*
  • Chenodeoxycholic Acid / pharmacokinetics
  • Computer Simulation
  • Glutamic Acid / chemistry
  • Glutamic Acid / metabolism
  • Glutamic Acid / pharmacokinetics
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Intestinal Mucosa / metabolism
  • Intestines / chemistry
  • Intestines / drug effects
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors
  • Organic Anion Transporters, Sodium-Dependent / chemistry*
  • Organic Anion Transporters, Sodium-Dependent / metabolism
  • Quantitative Structure-Activity Relationship
  • Regression Analysis
  • Stereoisomerism
  • Symporters / antagonists & inhibitors
  • Symporters / chemistry*
  • Symporters / metabolism


  • Organic Anion Transporters, Sodium-Dependent
  • Symporters
  • Chenodeoxycholic Acid
  • sodium-bile acid cotransporter
  • Glutamic Acid