The kinetic aspect of interactions of small molecules with their protein targets is increasingly recognized as being highly relevant for successful drug development. In light of the IMI project K4DD- �Kinetics for Drug Discovery�, we aim for gaining a deeper understanding of the structure-kinetics relationships of compounds at selected targets. In the first attempt to elucidate general trends in kinetic behavior, statistical modeling techniques were applied to a dataset of 180 compounds of HSP90 inhibitors derived from Surface Plasmon Resonance. Methods include histogram analysis, principal component analysis, decision trees, as well as self organizing maps. The trends observed in histogram analysis are pointing towards an influence of the molecular weight, the number of single bonds and the number of rings. This is in accordance with previously observed trends [1]. Building decision trees using a set of ADME related descriptors, led to predictive models, which allow to separating fast- from slow-dissociating compounds. The performance of the model is mainly influenced by the number of single bonds, number of hydrophobic atoms as well as number of aromatic atoms. (ROC: 0,852, MCC: 0,653) Further studies will focus on incorporation of descriptors encoding the flexibility of proteins. Acknowledgement: The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115366, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. More info: www.imi.europa.eu [1] Miller, Lunn, Jones, Med Chem. Comm., 3, 449-452 (2012)

Structure � kinetics relationship analysis of a set of HSP90 inhibitors

248th National Meeting (2014)

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