Balancing target flexibility and target denaturation in computational fragment-based inhibitor discovery
Copyright © 2012 Wiley Periodicals, Inc.
| Veröffentlicht in: | Journal of computational chemistry. - 1984. - 33(2012), 23 vom: 05. Sept., Seite 1880-91 |
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| Weitere Verfasser: | , |
| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2012
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| Zugriff auf das übergeordnete Werk: | Journal of computational chemistry |
| Schlagworte: | Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Interleukin-2 Ligands |
| Zusammenfassung: | Copyright © 2012 Wiley Periodicals, Inc. Accounting for target flexibility and selecting "hot spots" most likely to be able to bind an inhibitor continue to be challenges in the field of structure-based drug design, especially in the case of protein-protein interactions. Computational fragment-based approaches using molecular dynamics (MD) simulations are a promising emerging technology having the potential to address both of these challenges. However, the optimal MD conditions permitting sufficient target flexibility while also avoiding fragment-induced target denaturation remain ambiguous. Using one such technology (Site Identification by Ligand Competitive Saturation, SILCS), conditions were identified to either prevent denaturation or identify and exclude trajectories in which subtle but important denaturation was occurring. The target system used was the well-characterized protein cytokine IL-2, which is involved in a protein-protein interface and, in its unliganded crystallographic form, lacks surface pockets that can serve as small-molecule binding sites. Nonetheless, small-molecule inhibitors have previously been discovered that bind to two "cryptic" binding sites that emerge only in the presence of ligand binding, highlighting the important role of IL-2 flexibility. Using the above conditions, SILCS with hydrophobic fragments was able to identify both sites based on favorable fragment binding while avoiding IL-2 denaturation. An important additional finding was that acetonitrile, a water-miscible fragment, fails to identify either site yet can induce target denaturation, highlighting the importance of fragment choice |
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| Beschreibung: | Date Completed 03.06.2013 Date Revised 21.10.2021 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.23026 |