Technique for Generating Three-Dimensional Alignments of Multiple Ligands from One-Dimensional Alignments
| Autor: | Andrei Victor Anghelescu, Xiaoming Xie, Anthony E. Klon, Robert Kirk DeLisle, Jeffrey F. Lowrie, David J. Diller |
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| Rok vydání: | 2008 |
| Předmět: |
Receptors
CXCR3 biology Stereochemistry Chemistry General Chemical Engineering hERG Molecular Conformation General Chemistry Library and Information Sciences Lower dimensional space Ligands Estrogen Receptor Agonists Computer Science Applications Estrogen Receptor Antagonists Receptors Estrogen Potassium Channel Blockers biology.protein Biological system Algorithms |
| Zdroj: | Journal of Chemical Information and Modeling. 48:1041-1054 |
| ISSN: | 1549-960X 1549-9596 |
| Popis: | We describe and demonstrate a method for the simultaneous, fully flexible alignment of multiple molecules with a common biological activity. The key aspect of the algorithm is that the alignment problem is first solved in a lower dimensional space, in this case using the one-dimensional representations of the molecules. The three-dimensional alignment is then guided by constraints derived from the one-dimensional alignment. We demonstrate using 10 hERG channel blockers, with a total of 72 rotatable bonds, that the one-dimensional alignment is able to effectively isolate key conserved pharmacophoric features and that these conserved features can effectively guide the three-dimensional alignment. Further using 10 estrogen receptor agonists and 5 estrogen receptor antagonists with publicly available cocrystal structures we show that the method is able to produce superpositions comparable to those derived from crystal structures. Finally, we demonstrate, using examples from peptidic CXCR3 agonists, that the method is able to generate reasonable binding hypotheses. |
| Databáze: | OpenAIRE |
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