Surrogate AutoShim: Predocking into a Universal Ensemble Kinase Receptor for Three Dimensional Activity Prediction, Very Quickly, without a Crystal Structure
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- 作者：Eric J. Martin ; David C. Sullivan
- 刊名：Journal of Chemical Information and Modeling
- 出版年：2008
- 出版时间：April 2008
- 年：2008
- 卷：48
- 期：4
- 页码：873 - 881
- 全文大小：458K
- 年卷期：v.48,no.4(April 2008)
- ISSN：1549-960X
文摘
“Ensemble surrogate AutoShimȁd; is a kinase specific extension of the AutoShim docking method that solves the three traditional limitations of conventional docking: (1) it gives good correlations with affinity, (2) does not require a target protein structure, and (3) for a preprocessed company archive of 1.5 million compounds, is as fast as traditional 2D QSAR. It does require several hundred experimental IC50 values for each new target. Original AutoShim adds pharmacophore “shimsȁd; to a crystal structure binding site. An iterative partial least squares (PLS) procedure selects the best pose, while adjusting the shim weights to reproduce IC50 data. Surrogate AutoShim adjusts shims in one crystal structure to reproduce IC50 data for a different kinase target. Ensemble surrogate AutoShim uses 16 structurally diverse kinase crystal structures as a “universal ensemble kinase receptorȁd;, suitable for any kinase target. The 1.5 million member Novartis screening collection has been predocked into the shimmed ensemble, so new kinase models can be built, and the entire corporate archive virtually screened, in hours rather than weeks. A kinase-biased set of 10 000 compounds, that samples the entire corporate archive, has been designed for lead discovery by iterative kinase screening.