Inhibition Requirements of the Human Apical Sodium-Dependent Bile Acid Transporter (hASBT) Using Aminopiperidine Conjugates of glutamyl-Bile Acids
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Date
2009
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Abstract
Synthesize aminopiperidine conjugates of glutamyl-bile acids (glu-BAs) and develop a hASBT inhibition model using the conformationally sampled pharmacophore (CSP) approach.
glu-BAs aminopiperidine conjugates were synthesized. hASBT inhibition was measured as K-i. A CSP-SAR model was built using structural and physico-chemical descriptors and evaluated via cross-validation.
Twenty-nine aminopiperidine conjugates were synthesized. All inhibited hASBT, with K-i ranging from 0.95 to 31.8 mu M. Amidation of the piperidine nitrogen slightly decreased activity, while replacement by a carbon increased potency. Esterification of the glutamic acid linker had a minor impact, suggesting that a negative charge around C-24 is not required for binding. Three quantitative CSP-SAR models were developed. The best model (r (2) = 0.813, Q (2) = 0.726) included two descriptors: angle between 7-OH, alpha-substituent and centroid of rings B and C, and electrostatic contribution to the solvation free-energy. The model successfully distinguished between compounds with K-i < 16 mu M and K-i > 16 mu M. Models indicated that hydrophobicity, alpha substituent orientation, and partially compacted side chain conformation promote inhibitory potency. Qualitative CSP-SAR analysis indicated that the presence of an internal salt bridge, resulting in a locked conformation of the side chain, yielded weaker inhibitors.
Aminopiperidine conjugates of glu-BAs were potent hASBT inhibitors. A predictive and robust CSP-SAR model was developed.
glu-BAs aminopiperidine conjugates were synthesized. hASBT inhibition was measured as K-i. A CSP-SAR model was built using structural and physico-chemical descriptors and evaluated via cross-validation.
Twenty-nine aminopiperidine conjugates were synthesized. All inhibited hASBT, with K-i ranging from 0.95 to 31.8 mu M. Amidation of the piperidine nitrogen slightly decreased activity, while replacement by a carbon increased potency. Esterification of the glutamic acid linker had a minor impact, suggesting that a negative charge around C-24 is not required for binding. Three quantitative CSP-SAR models were developed. The best model (r (2) = 0.813, Q (2) = 0.726) included two descriptors: angle between 7-OH, alpha-substituent and centroid of rings B and C, and electrostatic contribution to the solvation free-energy. The model successfully distinguished between compounds with K-i < 16 mu M and K-i > 16 mu M. Models indicated that hydrophobicity, alpha substituent orientation, and partially compacted side chain conformation promote inhibitory potency. Qualitative CSP-SAR analysis indicated that the presence of an internal salt bridge, resulting in a locked conformation of the side chain, yielded weaker inhibitors.
Aminopiperidine conjugates of glu-BAs were potent hASBT inhibitors. A predictive and robust CSP-SAR model was developed.
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Keywords
apical sodium-dependent bile acid transporter, bile acid, CHARMM, conformationally sampled pharmacophore, transporter