Combining Global and Local Measures for Structure-Based Druggability Predictions
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- 作者：Andrea Volkamer ; Daniel Kuhn ; Thomas Grombacher ; Friedrich Rippmann ; Matthias Rarey
- 刊名：Journal of Chemical Information and Modeling
- 出版年：2012
- 出版时间：February 27, 2012
- 年：2012
- 卷：52
- 期：2
- 页码：360-372
- 全文大小：619K
- 年卷期：v.52,no.2(February 27, 2012)
- ISSN：1549-960X
文摘
Predicting druggability and prioritizing certain disease modifying targets for the drug development process is of high practical relevance in pharmaceutical research. DoGSiteScorer is a fully automatic algorithm for pocket and druggability prediction. Besides consideration of global properties of the pocket, also local similarities shared between pockets are reflected. Druggability scores are predicted by means of a support vector machine (SVM), trained, and tested on the druggability data set (DD) and its nonredundant version (NRDD). The DD consists of 1069 targets with assigned druggable, difficult, and undruggable classes. In 90% of the NRDD, the SVM model based on global descriptors correctly classifies a target as either druggable or undruggable. Nevertheless, global properties suffer from binding site changes due to ligand binding and from the pocket boundary definition. Therefore, local pocket properties are additionally investigated in terms of a nearest neighbor search. Local similarities are described by distance dependent histograms between atom pairs. In 88% of the DD pocket set, the nearest neighbor and the structure itself conform with their druggability type. A discriminant feature between druggable and undruggable pockets is having less short-range hydrophilic鈥揾ydrophilic pairs and more short-range lipophilic鈥搇ipophilic pairs. Our findings for global pocket descriptors coincide with previously published methods affirming that size, shape, and hydrophobicity are important global pocket descriptors for automatic druggability prediction. Nevertheless, the variety of pocket shapes and their flexibility upon ligand binding limit the automatic projection of druggable features onto descriptors. Incorporating local pocket properties is another step toward a reliable descriptor-based druggability prediction.