Establishing pharmacophore-centric proteome-wide structure-affinity relationships by chemical proteomics (ChemProtSAR)

• Applicants: Professor Dr. Bernhard Küster; Dr. Guillaume Médard
• Subject Area: Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation ; Pharmacy
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407391208

It has become very clear that most therapeutic drugs modulate the function of more than one protein. Therefore, repurposing a drug for a new medical indication in light of its other targets has emerged as an opportunistic but successful concept. However, most of the time, such new activities are only identified after years of use because current drug discovery approaches never investigate the full potential of a particular drug or the underlying pharmacophore. Chemical proteomics has emerged as a prime approach to delineate the target spectrum of small molecules without an a priori hypothesis and we have developed efficient workflows to systematically unravel drug repurposing opportunities of clinically investigated drugs. In this new interdisciplinary research proposal we will combine medicinal chemistry, biochemistry, mass spectrometry and bioinformatics to establish a pharmacophore-centric approach to drug discovery that systematically investigates the target space of any given small molecule on a proteome-wide scale to establish its structure-affinity relationship (SAR). More specifically, we will measure and compare the target profiles of a small library of one hundred structurally related molecules based on the same chemical scaffold with known inhibitory activity for kinase- and bromodomains which is equivalent to screening the library against thousands of native proteins simultaneously. This proof-of-concept study will:1) Demonstrate that prioritizing the comprehensiveness of the investigated targets over the size of the library of synthesized compounds procures a unique and efficient understanding of the molecular features involved in the observed cross-reactivities of the pharmacophore.2) Demonstrate that pharmacophore repurposing to hitherto untargeted proteins of biomedical significance can be approached systematically.3) Create an internet-based visualization tool allowing drug discovery scientists to explore and interact with this unprecedented dataset to form new biological and chemical hypothesis.The success of this endeavour shall prove that chemical proteomics can provide a much needed addition to the classical target-based (in which very few targets are investigated) and phenotypic-based (where target deconvolution is often difficult) drug discovery strategies. We anticipate that our pharmacophore-centric approach, which a priori fully characterizes the drug molecule with respect to its interaction with the proteome will provide datasets that can a posteriori be mined for a particular target of interest. This is of particular relevance in times when the advent of personalised medicine will require personalised drugs against non-classical and therefore typically untargeted proteins.

• DFG Programme: Research Grants