It has been realized that 'druglike' compounds often bind to multiple macromolecular targets. Consequently, predicting target profiles of hit and lead structure candidates has become both a challenge and an opportunity for computer-assisted drug design. No longer is ligand interaction with an individual target the sole objective in molecular design, but multi-dimensional functions guide in silico compound assembly and selection. We will present and discuss the concept of 'adaptive' fitness landscapes and their potential for drug discovery. The computational framework of this approach is based on data projection and Gaussian density estimation, which results in a probabilistic multi-dimensional 'SAR landscape' as a visual aid for compound prioritization. A related method employs self-organizing map representations of chemical space, which were successfully used for a selection of compounds exhibiting desired activity. Target profile prediction represents a consequent next step towards fully automated de novo drug design that satisfies multiple objectives in parallel. [1] Reutlinger, M.; Guba, W.; Martin, R. E.; Alanine, A. I.; Hoffmann, T.; Klenner, A.; Hiss, J. A.; Schneider, P.; Schneider, G. Neighborhood-preserving visualization of adaptive structure-activity landscapes and application to drug discovery. Angew. Chem. Int. Ed. 2011 , doi: 10.1002/anie.201105156.[2] Schneider, G.; Geppert, T.; Hartenfeller, M.; Reisen, F.; Klenner, A.; Reutlinger, M.; H�hnke, V.; Hiss, J. A.; Zettl, H.; Keppner, S.; Sp�nkuch, S.; Schneider, P. Reaction-driven de novo design, synthesis and testing of potential type II kinase inhibitors. Future Med. Chem. 2011 , 3, 415-424.[3] Schneider, P.; Stutz, K.; Kasper, L.; Haller, S.; Reutlinger, M.; Reisen, F.; Geppert, T.; Schneider, G. Target profile prediction for a Biginelli-type dihydropyrimidine compound library and practical evaluation. Pharmaceuticals 2011 , 4, 1236-1247.[4] Schneider, G.; Tanrikulu, Y.; Schneider, P. Self-organizing molecular fingerprints: a ligand-based view on drug-like chemical space and off-target prediction. Future Med. Chem. 2009 , 1, 213-28.

Where have all the good drugs gone?

243rd National Meeting (2012)

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