title: 4D-QSAR analysis of a series of antifungal p450 inhibitors and 3D-pharmacophore comparisons as a function of alignment.
abstract: A training set of 55 antifungal p450 analogue inhibitors was used to construct receptor-independent four-dimensional quantitative structure-activity relationship (RI 4D-QSAR) models. Ten different alignments were used to build the models, and one alignment yields a significantly better model than the other alignments. Two different methodologies were used to measure the similarity of the best 4D-QSAR models of each alignment. One method compares the residual of fit between pairs of models using the cross-correlation coefficient of their residuals of fit as a similarity measure. The other method compares the spatial distributions of the IPE types (3D-pharmacophores) of pairs of 4D-QSAR models from different alignments. Optimum models from several different alignments have nearly the same correlation coefficients, r(2), and cross-validation correlation coefficients, xv-r(2), yet the 3D-pharmacophores of these models are very different from one another. The highest 3D-pharmacophore similarity correlation coefficient between any pair of 4D-QSAR models from the 10 alignments considered is only 0.216. However, the best 4D-QSAR models of each alignment do contain some proximate common pharmacorphore sites. A test set of 10 compounds was used to validate the predictivity of the best 4D-QSAR models of each alignment. The "best" model from the 10 alignments has the highest predictivity. The inferred active sites mapped out by the 4D-QSAR models suggest that hydrogen bond interactions are not prevalent when this class of P450 analogue inhibitors binds to the receptor active site. This feature of the 4D-QSAR models is in agreement with the crystal structure results that indicate no ligand-receptor hydrogen bonds are formed.
authors: Laboratory of Molecular Modeling and Design (M/C 781), College of Pharmacy, The University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, USA.
authors: Jianzhong
authors: J
authors: Liu
authors: Dahua
authors: D
authors: Pan
authors: Yufeng
authors: Y
authors: Tseng
authors: Anton J
authors: AJ
authors: Hopfinger
mesh_terms: D000465:Algorithms; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors