RNA as a drug target is currently gaining a lot of interest, but not all of the right technologies are in place to successfully pursue it. In particular, access to experimentally determined structural information describing small molecule-RNA interactions is limited. ZoBio and our partner, the ETH Zürich, have been awarded a  €1.2 million EUREKA Eurostars grant to establish an automated pipeline enabling structure-based drug discovery (SBDD) using Nuclear Magnetic Resonance (NMR) for RNA targets. Whereas in the world of protein targeting drugs, X-ray crystallography has been the workhorse for obtaining structures, the highly flexible nature of most RNA targets makes them difficult or impossible to crystallize. Solution NMR offers the potential to avoid the necessity of crystals, but remains a complex, time demanding approach for RNA where high levels of expertise are needed. ZoBio and the research groups of Professors Peter Güntert and Roland Riek will use machine learning to automate the analysis of NMR data, a technology particularly well suited to cope with the flexible nature of RNA.

ZoBio has established a highly regarded NMR-based SBDD platform for protein targets that is complementary to crystallography. The platform integrates various software components for streamlining the NMR SBDD workflow including: automated data processing and analysis  and generation of structure models based on the NMR data. ZoBio will integrate the algorithms and procedures developed at the ETH and the unique know-how gained through the project into the existing platform to obtain a streamlined 3D structure determination pipeline for RNA–ligand complexes that is able to guide medicinal chemistry efforts in SBDD campaigns.

The ability to solve RNA structures in a suitable/actionable timeframe to support drug discovery projects using experimental data from a single sample will be groundbreaking. The software will work with a minimal amount of human intervention, reducing both the amount of time to acquire the data and the human resources to analyze and validate the results.

Ultimately, the project will lead to a research service that answers to the demand for structural biology that enables more efficient and, more importantly faster, development of small molecule drugs for RNA targets.

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