Docking and Three-dimensional Quantitative Structure-activity Relationship (3d Qsar) Analyses of Nonsteroidal Progesterone Receptor Ligands.
From: CSC, Scientific Computing Ltd., P.O. Box 405, FI-02101 Espoo, Finland. annu.soderholm@csc.fi
Journal of medicinal chemistry
- Publish Date: Jul 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 14
- Pages: 4261-8
- Medium: Print
- Language: English
- Citation (JAMA): Söderholm Annu A, Lehtovuori Pekka T, Nyrönen Tommi H, et al. Docking and Three-dimensional Quantitative Structure-activity Relationship (3d Qsar) Analyses of Nonsteroidal Progesterone Receptor Ligands.. J. Med. Chem. Jul 2006;49:4261-8
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.
Mesh Headings (Keywords): Binding Sites, Hydrogen Bonding, Ligands, Models, Molecular, Quantitative Structure-Activity Relationship, Quinolines, Receptors, Progesterone
Check for Full Text / PubMed Unique Identifier (PMID): 16821785
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