High-throughput pharmaceutical screening and structure-based inhibitor development

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High-throughput pharmaceutical screening and structure-based inhibitor development


Structure-based drug discovery is one of the most powerful techniques in modern drug discovery. Starting from the three-dimensional structure of drug targets, e.g. proteins essential for viral replication or host cell entry, different binding partners are typically proposed by computational predictions or initial considerations of compound properties and then tested for binding or even inhibition in biochemical and biophysical assays. Subsequently with assay screening, the previously identified compounds or comprehensive libraries of compounds are studied using X-ray crystallography to understand the nature of binding to the protein and the relationship between structure and function. Based on high-resolution structural data, compounds are then typically iteratively optimised to achieve higher binding affinities and inhibition of protein function, improve specificity or reduce toxicity. Our screening and compound optimisation approaches are supported by complementary methods such as mass spectrometry. This process of structure-based drug discovery, which begins with the selection of a target protein, the determination of the 3D structure and the selection of active substances for the target protein, and ends with (pre-) clinical testing, typically lasts several years.

High-throughput screening is commonly used in pharmaceutical research, where biochemical, genetic or pharmacological tests are performed on thousands to millions of compounds to find new biologically active substances from which lead structures can be derived to develop new drugs. Our group is pursuing the idea of starting these screenings directly from a structure-based level. By crystallising target proteins with fragment or compound libraries containing thousands of compounds, the actual binding process of these candidates can be visualised. This approach further leads to the opportunities of direct analysis of structure-activity relationships as well as the possibility of rational drug optimisation. In particular, the unique infrastructure on the DESY campus supports the sample throughput and our mission, which is to increase preparedness in case of future viral outbreaks. Currently, our studies focus on the inhibition of coronaviral proteases, coronaviral helicase, selected host cell proteases relevant in coronavirus infections, and enzymes of other novel RNA viruses.

Selected References

Günther, S., Reinke, P.Y.A., et al. (2021). X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science 372 (6542). DOI: 10.1126/science.abf7945

Günther, S., Reinke, P.Y.A., et al. (2020). Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease. bioRxiv. DOI: 10.1101/2020.05.02.043554