Dataset Information

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

ABSTRACT:

Purpose

Synthesize aminopiperidine conjugates of glutamyl-bile acids (glu-BAs) and develop a hASBT inhibition model using the conformationally sampled pharmacophore (CSP) approach.

Methods

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.

Results

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.

Conclusions

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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Publications

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]

PMID: 19384469

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Project description:Bile acids (BAs) are the end products of cholesterol metabolism. One of the critical steps in their biosynthesis involves the isomerization of the 3?-hydroxyl (-OH) group on the cholestane ring to the common 3?-configuration on BAs. BAs are actively recaptured from the small intestine by the human Apical Sodium-dependent Bile Acid Transporter (hASBT) with high affinity and capacity. Previous studies have suggested that no particular hydroxyl group on BAs is critical for binding or transport by hASBT, even though 3?-hydroxylated BAs were not examined. The aim of this study was to elucidate the role of the 3?-OH group on BAs binding and translocation by hASBT. Ten 3?-hydroxylated BAs (Iso-bile acids, iBAs) were synthesized, characterized, and subjected to hASBT inhibition and uptake studies. hASBT inhibition and uptake kinetics of iBAs were compared to that of native 3?-OH BAs. Glycine conjugates of native and isomeric BAs were subjected to molecular dynamics simulations to identify topological descriptors related to binding and translocation by hASBT. Iso-BAs bound to hASBT with lower affinity and exhibited reduced translocation than their respective 3?-epimers. Kinetic data suggests that, in contrast to native BAs where hASBT binding is the rate-limiting step, iBAs transport was rate-limited by translocation and not binding. Remarkably, 7-dehydroxylated iBAs were not hASBT substrates, highlighting the critical role of 7-OH group on BA translocation by hASBT, especially for iBAs. Conformational analysis of gly-iBAs and native BAs identified topological features for optimal binding as: concave steroidal nucleus, 3-OH "on-" or below-steroidal plane, 7-OH below-plane, and 12-OH moiety toward-plane. Our results emphasize the relevance of the 3?-OH group on BAs for proper hASBT binding and transport and revealed the critical role of 7-OH group on BA translocation, particularly in the absence of a 3?-OH group. Results have implications for BA prodrug design.

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Dataset Information

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

Purpose

Methods

Results

Conclusions

Publications

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

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