Serveral ongoing projects were made possible thanks to the following programs;
NIH is the nation’s medical research agency—supporting scientific studies that turn discovery into health.
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 aminoacid 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 ceter of PPI interfaces. These anchor residues are often deeply burried 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 indepth 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 relvant PPI p53/mdm2 and p53/mdm4 where we used Trp as a central anchor fragment in the design of antagonists.
The herein syntheszied 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 diabetis, cancer and Alzheimers disease.
RO1 (NIH), ANCHOR: A PDB – Wide Real Time Discovery Resource of Novel Protein – Protein Interaction (Ant)‐agonists PI Carlos Camacho, CO-PI Alexander Dömling (equivalent)
Current chemical biology collaborations are mainly based on high-throughput -screening of large libraries of commercially existing compounds on targets of biological interest. However, this fix modality fails to provide much synergy between these two mature disciplines, i.e., chemistry and biology and often requires prior funding. We propose to develop a radically new open access – sic democratic – technology to facilitate the true collaboration amongst biologists, say, experts on specific protein‐protein interactions (PPIs) and chemists who are interested in the rational development of protein interaction small molecular weight (ant)agonists. Specifically, we seek to benefit from the growing structural information on protein-protein interactions (PPIs), exemplified in the Protein Data Bank (PDB), to develop a PDB wide – sic system biology – approach that combine biophysical insights with multiple component reaction (MCR) chemistry to develop and screen million-size virtual libraries of chemically accessible novel compounds with the ultimate goal to develop drugs for unmet medical needs, e.g. cancer, Alzheimer’s and orphan diseases.
The European Lead Factory is a pan-European platform for drug discovery supported by the Innovative Medicines Initiative (IMI) that is set to give a major boost to drug discovery in Europe. Comprising a collection of half a million compounds (derived from new public and existing private company collections) and a screening centre, the European Lead Factory will offer researchers in academia, small and medium-sized enterprises (SMEs) and patient organisations an unprecedented opportunity to advance medical research and develop new medicines.
Innovative Medicines Initiatives (IMI): EU Lead Factory, Member of the winning consortium (01.01.2013-31.12.2017)