title: Docking and three-dimensional quantitative structure-activity relationship (3D QSAR) analyses of nonsteroidal progesterone receptor ligands.
abstract: We report a docking and comparative molecular similarity indices analysis (CoMSIA) study of progesterone receptor (PR) ligands with an emphasis on nonsteroids including tanaproget. The ligand alignment generation, a critical part of model building, comprised two stages. First, thorough conformational sampling of docking poses within the PR binding pocket was made with the program GOLD. Second, a strategy to select representative poses for CoMSIA was developed utilizing the FlexX scoring function. After manual replacement of five poses where this approach had problems, a significant correlation (r(2) = 0.878) between the experimental affinities and electrostatic, hydrophobic, and hydrogen bond donor properties of the aligned ligands was found. Extensive model validation was made using random-group cross-validations, external test set predictions (r(pred)(2) = 0.833), and consistency check between the CoMSIA model and the PR binding site structure. Robustness, predictive ability, and automated alignment generation make the model a potential tool for virtual screening.
authors.affiliation: CSC, Scientific Computing Ltd., P.O. Box 405, FI-02101 Espoo, Finland. annu.soderholm@csc.fi
authors.forename: Annu A
authors.initials: AA
authors.lastname: Söderholm
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Lehtovuori
authors.forename: Tommi H
authors.initials: TH
authors.lastname: Nyrönen
mesh_terms: D001665:Binding Sites; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry*; D011980:Receptors, Progesterone / Q000737:chemistry*
chemical_list: D008024:Ligands; D011804:Quinolines; D011980:Receptors, Progesterone