The P41 grant proposal (Pilot-Scale Libraries (PSL) for High-Throughput Screening) titled """"""""Protein protein interaction directed compound libraries"""""""" will produce 1,760 compounds based on 56 scaffolds aiming to (ant-) agonize protein protein interaction (PPI). It is well established that PPI interfaces - although not easily to categorize - do not have random amino acid distribution. In fact many PPIs have a higher than average Phe, Trp and Leu content and these are the most abundant amino acids in the center of PPI interfaces. These anchor residues are often deeply hurried in the interfaces and contribute much of the energy of interaction of the two proteins. Those energetically important sites are often called """"""""hot-spot"""""""". Based on our in depth analysis of many PPI Interfaces containing Trp, Phe and Leu we herein propose that small molecule libraries containing Trp,Phe and Leu fragments should have a much larger probability to (ant-)agonize PPIs than usual screening libraries. This is also based on our recent success of finding very potent antagonists for the cancer relevant PPI p53/mdm2 and p53/mdm4 where we used Trp as a central anchor fragment in the design of antagonists. The herein synthesized compounds will complement current screening libraries of the MLSMR by likely targeting protein protein interactions. Protein interactions are involved in all disease relevant pathways and are of uttermost importance to understand for the future design of novel drugs to address unmet medical needs, such as diabetes, cancer and Alzheimer's disease.
The proposal addresses the RFA by providing compounds which are designed to (ant-)agonize protein protein interaction. The libraries most likely will result in novel biological patterns and lead to further follow on projects aiming to deconvolute their mode-of-actions. The compounds are of high analytical quality, novel, diverse and biologically inspired.
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| Neochoritis, Constantinos G; Zarganes-Tzitzikas, Tryfon; Stotani, Silvia et al. (2015) Leuckart-Wallach Route Toward Isocyanides and Some Applications. ACS Comb Sci 17:493-9 |
| Zak, Krzysztof M; Kitel, Radoslaw; Przetocka, Sara et al. (2015) Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1. Structure 23:2341-2348 |
| Boltjes, André; Huang, Yijun; van de Velde, Rob et al. (2014) Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor. ACS Comb Sci 16:393-6 |
| Dömling, Alexander; Holak, Tad A (2014) Programmed death-1: therapeutic success after more than 100?years of cancer immunotherapy. Angew Chem Int Ed Engl 53:2286-8 |
| Huang, Yijun; Wolf, Siglinde; Beck, Barbara et al. (2014) Discovery of highly potent p53-MDM2 antagonists and structural basis for anti-acute myeloid leukemia activities. ACS Chem Biol 9:802-11 |
| Neochoritis, Constantinos G; Dömling, Alexander (2014) Towards a facile and convenient synthesis of highly functionalized indole derivatives based on multi-component reactions. Org Biomol Chem 12:1649-51 |
| Bista, Michal; Wolf, Siglinde; Khoury, Kareem et al. (2013) Transient protein states in designing inhibitors of the MDM2-p53 interaction. Structure 21:2143-51 |
| Sinha, Mantosh K; Khoury, Kareem; Herdtweck, Eberhardt et al. (2013) Tricycles by a new Ugi variation and Pictet-Spengler reaction in one pot. Chemistry 19:8048-52 |
| Sinha, Mantosh K; Khoury, Kareem; Herdtweck, Eberhardt et al. (2013) Various cyclization scaffolds by a truly Ugi 4-CR. Org Biomol Chem 11:4792-6 |
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