3D-QSAR model for inhibition requirements for hASBT using glutamyl-chenodeoxycholate (glu-CDCA) conjugates of aniline

COMP 195

Chayan Acharya, Rana Rais, James E. Polli, and Alexander D. MacKerell Jr. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, 20 Penn Street, Baltimore, MD 21201
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.

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

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009