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Ensemble docking into multiple crystallographically derived protein structures: an evaluation based on the statistical analysis of enrichments

Ensemble docking into multiple crystallographically derived protein structures: an evaluation based on the statistical analysis of enrichments
Ensemble docking into multiple crystallographically derived protein structures: an evaluation based on the statistical analysis of enrichments
Docking into multiple receptor conformations (“ensemble docking”) has been proposed, and employed, in the hope that it may account for receptor flexibility in virtual screening and thus provide higher enrichments than docking into single rigid receptor structures. The statistical analyses presented in this paper provide quantitative evidence that in some cases docking into a crystallographically derived conformational ensemble does indeed yield better enrichment than docking into any of the individual members of the ensemble. However, these “successful” ensembles account for only a minority of those examined and it would not have been possible to prospectively predict their identity using only protein structural information. A more frequently observed outcome is that the ensemble enrichment is higher than the mean of the enrichments provided by its individual members. An additional and promising finding is that, if a set of known active compounds is available, an approach based on induced-fit docking appears to be a reliable way to construct ensembles which provide relatively high enrichments.
1549-9596
511-524
Craig, Ian R.
47fd7541-0862-4f53-a397-55cb1577248d
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Spiegel, Katrin
b1e9b7d9-579f-40c6-b9f8-1ba904fe7a0b
Craig, Ian R.
47fd7541-0862-4f53-a397-55cb1577248d
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Spiegel, Katrin
b1e9b7d9-579f-40c6-b9f8-1ba904fe7a0b

Craig, Ian R., Essex, Jonathan W. and Spiegel, Katrin (2010) Ensemble docking into multiple crystallographically derived protein structures: an evaluation based on the statistical analysis of enrichments. Journal of Chemical Information and Modeling, 50 (4), 511-524. (doi:10.1021/ci900407c). (PMID:20222690)

Record type: Article

Abstract

Docking into multiple receptor conformations (“ensemble docking”) has been proposed, and employed, in the hope that it may account for receptor flexibility in virtual screening and thus provide higher enrichments than docking into single rigid receptor structures. The statistical analyses presented in this paper provide quantitative evidence that in some cases docking into a crystallographically derived conformational ensemble does indeed yield better enrichment than docking into any of the individual members of the ensemble. However, these “successful” ensembles account for only a minority of those examined and it would not have been possible to prospectively predict their identity using only protein structural information. A more frequently observed outcome is that the ensemble enrichment is higher than the mean of the enrichments provided by its individual members. An additional and promising finding is that, if a set of known active compounds is available, an approach based on induced-fit docking appears to be a reliable way to construct ensembles which provide relatively high enrichments.

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Published date: 11 March 2010

Identifiers

Local EPrints ID: 179885
URI: http://eprints.soton.ac.uk/id/eprint/179885
ISSN: 1549-9596
PURE UUID: 7930119f-014f-4206-a6c7-9472a63c9627
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 06 Apr 2011 13:18
Last modified: 03 Dec 2019 02:02

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Contributors

Author: Ian R. Craig
Author: Katrin Spiegel

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