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Can we use docking and scoring for hit-to-lead optimization?

Enyedy, Istvan and Egan, William (2008) Can we use docking and scoring for hit-to-lead optimization? Journal of Computer-Aided Molecular Design, 22 (3-4). pp. 161-168. ISSN 0920-654X


Docking and scoring is currently one of the tools used for hit finding and hit-to-lead optimization when structural information about the target is known. Docking scores have been found useful for optimizing ligand binding to reproduce experimentally observed binding modes. The question is, can docking and scoring be used reliably for hit-to-lead optimization? To illustrate the challenges of scoring for hit-to-lead optimization, the relationship of docking scores with experimentally determined IC(50) values measured in-house were tested. The influences of the particular target, crystal structure, and the precision of the scoring function on the ability to differentiate between actives and inactives were analyzed by calculating the area under the curve of receiver operator characteristic curves for docking scores. It was found that for the test sets considered, MW and sometimes ClogP were as useful as GlideScores and no significant difference was observed between SP and XP scores for differentiating between actives and inactives. Interpretation by an expert is still required to successfully utilize docking and scoring in hit-to-lead optimization.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Docking and scoring; Glide; Hit optimization; ROC analysis; Kinase; KDR; CDK2; ABL
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Date Deposited: 14 Dec 2009 13:51
Last Modified: 14 Dec 2009 13:51


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