Inhibition Requirements of the Human Apical Sodium-Dependent Bile Acid Transporter (hASBT) Using Aminopiperidine Conjugates of glutamyl-Bile Acids

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dc.contributor.authorGonzalez, Pablo M.
dc.contributor.authorAcharya, Chayan
dc.contributor.authorMacKerell, Alexander D., Jr.
dc.contributor.authorPolli, James E.
dc.date.accessioned2025-01-21T00:08:41Z
dc.date.available2025-01-21T00:08:41Z
dc.date.issued2009
dc.description.abstractSynthesize aminopiperidine conjugates of glutamyl-bile acids (glu-BAs) and develop a hASBT inhibition model using the conformationally sampled pharmacophore (CSP) approach.
dc.description.abstractglu-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.
dc.description.abstractTwenty-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.
dc.description.abstractAminopiperidine conjugates of glu-BAs were potent hASBT inhibitors. A predictive and robust CSP-SAR model was developed.
dc.fuente.origenWOS
dc.identifier.doi10.1007/s11095-009-9877-3
dc.identifier.eissn1573-904X
dc.identifier.issn0724-8741
dc.identifier.urihttps://doi.org/10.1007/s11095-009-9877-3
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/95679
dc.identifier.wosidWOS:000266585900012
dc.issue.numero7
dc.language.isoen
dc.pagina.final1678
dc.pagina.inicio1665
dc.revistaPharmaceutical research
dc.rightsacceso restringido
dc.subjectapical sodium-dependent bile acid transporter
dc.subjectbile acid
dc.subjectCHARMM
dc.subjectconformationally sampled pharmacophore
dc.subjecttransporter
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleInhibition Requirements of the Human Apical Sodium-Dependent Bile Acid Transporter (hASBT) Using Aminopiperidine Conjugates of glutamyl-Bile Acids
dc.typeartículo
dc.volumen26
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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