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Seebeck B.,University of Hamburg | Wagener M.,Molecular Design and Informatics | Rarey M.,University of Hamburg
ChemMedChem | Year: 2011

The role of activity cliffs in drug discovery projects is certainly two-edged: on the one hand, they often lead to the failure of QSAR modeling techniques; on the other, they are highly valuable for identifying key aspects of SARs. In the presence of activity cliffs the results of purely ligand-based QSAR approaches often remain puzzling, and the resulting models have limited predictive power. Herein we present a new approach for the identification of structure-based activity cliffs (ISAC). It uses the valuable information of activity cliffs in a structure-based design scenario by analyzing interaction energies of protein-ligand complexes. Using the relative frequency at which a protein atom is involved in activity cliff events, we introduce a novel visualization of hot spots in the active site of a protein. The ISAC approach supports the medicinal chemist in elucidating the key interacting atoms of the binding site and facilitates the development of pharmacophore hypotheses. The hot spot visualization can be applied to small data sets in early project phases as well as in the lead optimization process. Based on the ISAC approach, we developed a method to derive target-specific scoring functions and pharmacophore constraints, which were validated on independent external data sets in virtual screening experiments. The activity-cliff-based approach shows an improved enrichment over the generic empirical scoring function for various protein targets in the validation set. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dwyer M.P.,Merck And Co. | Keertikar K.,Merck And Co. | Paruch K.,Merck And Co. | Alvarez C.,Merck And Co. | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

The synthesis and hit-to-lead SAR development from a pyrazolo[1,5-a] pyrimidine-derived hit 5 to the identification of a series of potent, pan-Pim inhibitors such as 11j are described. © 2013 Elsevier Ltd. All rights reserved.

Fleuren W.W.M.,Radboud University Nijmegen | Fleuren W.W.M.,Netherlands Bioinformatics Center | Verhoeven S.,Molecular Design and Informatics | Frijters R.,Radboud University Nijmegen | And 4 more authors.
Nucleic Acids Research | Year: 2011

In this article, we present CoPub 5.0, a publicly available text mining system, which uses Medline abstracts to calculate robust statistics for keyword co-occurrences. CoPub was initially developed for the analysis of microarray data, but we broadened the scope by implementing new technology and new thesauri. In CoPub 5.0, we integrated existing CoPub technology with new features, and provided a new advanced interface, which can be used to answer a variety of biological questions. CoPub 5.0 allows searching for keywords of interest and its relations to curated thesauri and provides highlighting and sorting mechanisms, using its statistics, to retrieve the most important abstracts in which the terms co-occur. It also provides a way to search for indirect relations between genes, drugs, pathways and diseases, following an ABC principle, in which A and C have no direct connection but are connected via shared B intermediates. With CoPub 5.0, it is possible to create, annotate and analyze networks using the layout and highlight options of Cytoscape web, allowing for literature based systems biology. Finally, operations of the CoPub 5.0 Web service enable to implement the CoPub technology in bioinformatics workflows. CoPub 5.0 can be accessed through the CoPub portal http://www.copub.org. © 2011 The Author(s).

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