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Inhibition requirements of the human apical sodium-dependent bile acid transporter (hASBT) using aminopiperidine conjugates of glutamyl-bile acids.


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 muM. 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) < 16muM and K(i) > 16muM. 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.

SUBMITTER: Gonzalez PM 

PROVIDER: S-EPMC2882941 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Inhibition requirements of the human apical sodium-dependent bile acid transporter (hASBT) using aminopiperidine conjugates of glutamyl-bile acids.

González Pablo M PM   Acharya Chayan C   Mackerell Alexander D AD   Polli James E JE  

Pharmaceutical research 20090421 7


<h4>Purpose</h4>Synthesize aminopiperidine conjugates of glutamyl-bile acids (glu-BAs) and develop a hASBT inhibition model using the conformationally sampled pharmacophore (CSP) approach.<h4>Methods</h4>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.<h4>Results</h4>Twenty-nine aminopiperidine conjugates were synthesized. All inhibited hASBT,  ...[more]

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