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Brief Bioinform. 2018 Oct 31. doi: 10.1093/bib/bby103. [Epub ahead of print]

Comprehensive assessment of nine docking programs on type II kinase inhibitors: prediction accuracy of sampling power, scoring power and screening power.

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College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P. R. China.
State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health,Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau (SAR), P. R. China.
Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu, P. R. China.
Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, P. R. China.
State Key Lab of CAD&CG, Zhejiang University, Hangzhou, Zhejiang, P. R. China.


Protein kinases have been regarded as important therapeutic targets for many diseases. Currently, a total of 41 kinase inhibitors have been approved by the Food and Drug Administration, along with a large number of kinase inhibitors being evaluated in clinical and preclinical trials. Among all, allosteric inhibitors, such as type II kinase inhibitors, have attracted extensive attention owing to their potential high selectivity. Nowadays, molecular docking has become a powerful tool to search for novel kinase inhibitors. However, as for type II kinase inhibitors, their allosteric characteristics may exert a deep influence on docking accuracy. In this study, a comprehensive assessment was conducted to evaluate the effectiveness of nine docking algorithms towards type II kinase inhibitors. The calculation results showed that most tested docking programs, especially Glide with XP scoring, LeDock and Surflex-Dock, succeeded in the accurate identification of near-native binding poses, with the success rates ranging from 0.80 to 0.90, and the scoring functions in GOLD and LeDock outperformed the others in the prediction of relative binding affinities. In terms of the P-values, areas under the curve and enrichment factors, Glide with XP scoring, Surflex-Dock, GOLD with Astex Statistical Potential scoring and LeDock had better screening power to discriminate between active compounds and decoys. However, the screening power is sensitive to different initial conformations of the same target. It is expected that our study can provide some guidance for docking-based virtual screening to discover novel type II kinase inhibitors, as well as other allosteric inhibitors.


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