COMP 195 |
| Inhibition of human apical sodium-dependent bile acid transporter (hASBT) was evaluated using substituted aniline conjugates of glu-CDCA. Compound inhibitory values, Ki, were measured by testing compounds at various concentrations, using taurocholate as a substrate and stably transfected hASBT-MDCK monolayers. The in silico models of compounds were built using all-atom CHARMM General Force Field. A 3D-QSAR model for hASBT inhibition using conformationally sampled pharmacophore method (CSP-SAR) was built using the 1-D and 2-D probability distributions of various structural descriptors obtained from MD simulations. CSP-SAR models were selected based on multivariable regression and Akaike Information Criterion (AIC) analysis. Models were evaluated by the leave-one-out cross validation method. Interestingly, 2 and 3-amino benzoic acid glu-CDCA allow intramolecular hydrogen bonding, promoting compound potency; while 4-amino benzoic acid lacked intramolecular hydrogen bond resulting in poor binding affinity. Aniline conjugates of glutamyl-CDCAs were potent inhibitors of hASBT. A highly predictive and robust hASBT-inhibition CSP-SAR model was developed and considers compound hydrophilicity and intramolecular hydrogen bonding on compound activity. |
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Poster Session
6:00 PM-8:00 PM, Tuesday, August 18, 2009 Walter E. Washington Convention Center -- Ballroom A, Poster
Division of Computers in Chemistry |