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Comparative virtual screening and novelty detection for NMDA-GlycineB antagonists

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Abstract

Identification of novel compound classes for a drug target is a challenging task for cheminformatics and drug design when considerable research has already been undertaken and many potent lead structures have been identified, which leaves limited unclaimed chemical space for innovation. We validated and successfully applied different state-of-the-art techniques for virtual screening (Bayesian machine learning, automated molecular docking, pharmacophore search, pharmacophore QSAR and shape analysis) of 4.6 million unique and readily available chemical structures to identify promising new and competitive antagonists of the strychnine-insensitive Glycine binding site (GlycineB site) of the NMDA receptor. The novelty of the identified virtual hits was assessed by scaffold analysis, putting a strong emphasis on novelty detection. The resulting hits were tested in vitro and several novel, active compounds were identified. While the majority of the computational methods tested were able to partially discriminate actives from structurally similar decoy molecules, the methods differed substantially in their prospective applicability in terms of novelty detection. The results demonstrate that although there is no single best computational method, it is most worthwhile to follow this concept of focused compound library design and screening, as there still can new bioactive compounds be found that possess hitherto unexplored scaffolds and interesting variations of known chemotypes.

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Acknowledgments

Dr. Manuela López de la Paz, Dr. Udo Meyer and Dr. Lutz Franke are thanked for valuable discussions. Swetlana Derksen is thanked for help in the compilation of literature references. The in vitro screening department at Merz Pharmaceuticals, especially Dr. Meik Sladek, Dr. Claudia Jatzke, Tanja Bauer and Christina Wollenburg are thanked for the in vitro screening of our compounds and stimulating and most helpful discussion.

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Correspondence to Bjoern A. Krueger or Gisbert Schneider.

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Krueger, B.A., Weil, T. & Schneider, G. Comparative virtual screening and novelty detection for NMDA-GlycineB antagonists. J Comput Aided Mol Des 23, 869–881 (2009). https://doi.org/10.1007/s10822-009-9304-1

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