Docking-undocking combination applied to the D3R Grand Challenge 2015

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• 作者：Sergio Ruiz-Carmona ; Xavier Barril
• 关键词：D3R ; Drug discovery data resource ; Grand Challenge ; Docking ; Dynamic ; Undocking ; GC2015 ; Protein flexibility
• 刊名：Journal of Computer-Aided Molecular Design
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：30
• 期：9
• 页码：805-815
• 全文大小：1,264 KB
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Physical Chemistry
  Computer Applications in Chemistry
  Animal Anatomy, Morphology and Histology
  
• 出版者：Springer Netherlands
• ISSN：1573-4951
• 卷排序：30

文摘

Novel methods for drug discovery are constantly under development and independent exercises to test and validate them for different goals are extremely useful. The drug discovery data resource (D3R) Grand Challenge 2015 offers an excellent opportunity as an external assessment and validation experiment for Computer-Aided Drug Discovery methods. The challenge comprises two protein targets and prediction tests: binding mode and ligand ranking. We have faced both of them with the same strategy: pharmacophore-guided docking followed by dynamic undocking (a new method tested experimentally here) and, where possible, critical assessment of the results based on pre-existing information. In spite of using methods that are qualitative in nature, our results for binding mode and ligand ranking were amongst the best on Hsp90. Results for MAP4K4 were less positive and we track the different performance across systems to the level of previous knowledge about accessible conformational states. We conclude that docking is quite effective if supplemented by dynamic undocking and empirical information (e.g. binding hot spots, productive protein conformations). This setup is well suited for virtual screening, a frequent application that was not explicitly tested in this edition of the D3R Grand Challenge 2015. Protein flexibility remains as the main cause for hard failures.