Computational modeling of apical sodium dependent bile acid
transporter
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The apical sodium-dependent bile acid transporter (ASBT) and its role in bile acid absorption in the terminal ileum. It also explores the potential risks associated with drugs that inhibit ASBT, such as an increased risk of colon cancer. The document delves into the evaluation of BAT inhibition and the use of models to screen a database of drugs to prioritize compounds for testing. The most potent inhibitors of ASBT were found to be dihydropyridine calcium channel blockers and HMG-CoA reductase inhibitors. The document also discusses a pharmacophore model developed based on a training set of 17 chemically diverse inhibitors of ASBT.
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2020/2021
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Computational modeling of apical sodium dependent bile acid transporter
INTRODUCTION
- (^) Bile acids are primarily absorbed in the terminal ileum by active uptake via the apical sodium-dependent bile acid transporter (ASBT; SLC10A2)
- (^) The human apical sodium-dependent bile acid transporter (ASBT; SLC10A2) is the primary mechanism for intestinal bile acid re- absorption
- (^) 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.
BILE ACID TRANSPORTER NAME TISSUE FUNCTION/SUBSTRATE Na+/Taurocholate Co-transporting Polypeptide (NTCP/SLC10A1) liver (sinusoidal) Transports Conjugate & unconjugate bile acids from blood into liver (Na+ dependent SAT) Drugs - Rosuvastatin Apical Na+ Dependent bile acid transporter (ASBT, SLC10A2) Distal small intestine (apical) Uptake of bile acids from intestinal lumen 1.
OSTα-OSTβ^ Small intestine (apical), liver (sinusoidal) Enterohepatic recirculation of bile acids- efflux of bile acids & conjugate steroids (intestinal epithelia →→ circulation) Drugs- Digoxin, Rosuvastatin
Bile Acid Transporter Inhibitors
- (^) Inhibitors - Cyclosporine, Rifampicin, Glibenclamide, Troglitazone inhibition of BAT intracellular accumulation of cytotoxic bile salts Cholestasis & Hepatotoxicity
- (^) Evaluation of BAT inhibition important role in identification of compounds that could be a potential cause of cholestasis.
ASBT
- (^) The human apical sodium-dependent bile acid transporter (ASBT) is a high_x0002_efficacy, high-capacity transporter expressed on the apical membrane of intestinal epithelial cells and cholangiocytes. It assists absorption of bile acids and their analogs, thus providing an additional intestinal target for improving drug absorption. Baringhaus and colleagues developed a pharmacophore model based on a training set of 17 chemically diverse inhibitors of ASBT.
- (^) The model revealed ASBT transport requirements as one hydrogen bond donor, one hydrogen bond acceptor, one negative charge, and three hydrophobic centers. These requirements are in good agreement with a previous 3D-QSAR model derived from the structure and activity of 30 ASBT inhibitors and substrates.