title: Computational models for drug inhibition of the human apical sodium-dependent bile acid transporter.
abstract: The human apical sodium-dependent bile acid transporter (ASBT; SLC10A2) is the primary mechanism for intestinal bile acid reabsorption. In the colon, secondary bile acids increase the risk of cancer. Therefore, drugs that inhibit ASBT have the potential to increase the risk of colon cancer. The objectives of this study were to identify FDA-approved drugs that inhibit ASBT and to derive computational models for ASBT inhibition. Inhibition was evaluated using ASBT-MDCK monolayers and taurocholate as the model substrate. Computational modeling employed a HipHop qualitative approach, a Hypogen quantitative approach, and a modified Laplacian Bayesian modeling method using 2D descriptors. Initially, 30 compounds were screened for ASBT inhibition. A qualitative pharmacophore was developed using the most potent 11 compounds and applied to search a drug database, yielding 58 hits. Additional compounds were tested, and their K(i) values were measured. A 3D-QSAR and a Bayesian model were developed using 38 molecules. The quantitative pharmacophore consisted of one hydrogen bond acceptor, three hydrophobic features, and five excluded volumes. Each model was further validated with two external test sets of 30 and 19 molecules. Validation analysis showed both models exhibited good predictability in determining whether a drug is a potent or nonpotent ASBT inhibitor. The Bayesian model correctly ranked the most active compounds. In summary, using a combined in vitro and computational approach, we found that many FDA-approved drugs from diverse classes, such as the dihydropyridine calcium channel blockers and HMG CoA-reductase inhibitors, are ASBT inhibitors.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.
authors: Xiaowan
authors: X
authors: Zheng
authors: Sean
authors: S
authors: Ekins
authors: Jean-Pierre
authors: JP
authors: Raufman
authors: James E
authors: JE
authors: Polli
mesh_terms: D000818:Animals; D001185:Artificial Intelligence; D001499:Bayes Theorem; D001647:Bile Acids and Salts / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D003110:Colonic Neoplasms / Q000209:etiology; D004232:Diuretics / Q000737:chemistry / Q000633:toxicity; D004285:Dogs; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000633:toxicity; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D008958:Models, Molecular; D015233:Models, Statistical; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D012307:Risk Factors; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014162:Transfection
chemical_list: D001647:Bile Acids and Salts; D002121:Calcium Channel Blockers; D004232:Diuretics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D029363:Organic Anion Transporters, Sodium-Dependent; D011994:Recombinant Proteins; D027981:Symporters; C071908:sodium-bile acid cotransporter