The investigation of protein-ligand interactions is one of the prerequisites for structure-based design of small molecule modulators of protein function. These interactions can be regarded based on structural similarity of secondary structure elements with impact on rational drug design [1]. The basic idea of the presented approach is the fact that a similar spatial arrangement of secondary structure elements around the binding site (‘ligand-sensing cores’) can recognize similar scaffolds independent of the overall fold [2]. The discovery of Namoline as a lysine-specific demethylase inhibitor, which impairs the growth of prostate cancer cells, by Willmann et al. demonstrated the pharmaceutical relevance of this concept [3]. However, to date there is no automated procedure available to compare 'ligand-sensing cores' of various proteins. We will present the results of our ongoing progress to develop an automated computational method to identify similar 'ligand-sensing cores' in binding pockets of otherwise unrelated proteins for all known protein structures. Our approach is based on labelled graphs generated based on the secondary structure information provided by Secbase [4], an extension module of the Relibase. Calculations on available test datasets reveal a robust and very fast implementation, so that an all-against-all comparisons of the whole PDB should be possible within one or two months of calculation time on a recent workstation. We are currently optimizing our approach on several datasets and have also generated very promising results on ATP and other target specific datasets recently. We will also present the results of the all-against-all comparison. In the end, this information of all similar ligand-sensing cores within all known protein structures will provide access to previously unused data to predict polypharmacology and to identify new lead structures. Therefore, this development leads to a valuable tool for rational structure-based drug design. [1] Koch O; In Future Medicinal Chemistry; 2011:699-708. [2] Koch M A, Waldmann H; In Drug Discovery Today; 2005:471-483. [3] Willmann D, Lim S, Wetzel S, Metzger E, Jandrausch A, Wilk W, Jung M, Forne I, Imhof A, Janzer A, Kirfel J, Waldmann H, Schüle R, Buettner R; In International Journal of Cancer; 2012:2704-2709 [4] Koch O, Cole J, Block P, Klebe G; J. Chem. Inf. Model; 2009:2388-2402

On our way to the automated search for ligand-sensing cores

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.