Industrial clients at ESRF fast-track drug discovery

It all started with a molecule that bound weakly to the SARS-CoV-2, the virus responsible for COVID-19. “About two year ago, we had identified this molecule, a diazepane scaffold, through artificial intelligence and computational screening and thought we would investigate further”, explains Julien Hazemann, first author of the publication and former researcher at Idorsia. The compound could potentially inhibit the virus’s main protease (Mpro)—a critical enzyme for viral replication.

In order to increase the efficiency of the molecule, so that it would bind to Mpro, the team from Idorsia used computational simulations, high-throughput chemistry and structural biology at the ESRF in collaboration with the company Expose GmbH. This approach, called hit-to-lead optimisation, has been used in antiviral drug discovery in the last ten years, but it is the first time that the techniques were integrated in such a tight and effective way in a global effort.  

First, the researchers employed computational docking and molecular dynamics simulations to predict how structural changes to the molecule might improve binding to Mpro.

Using high-throughput medicinal chemistry, they synthesized and tested a focused library of analogues. These steps led to a dramatic improvement of the original compound to a nearly 1,000-fold increase in potency.

However, predicting how a molecule behaves computationally was only one piece of the puzzle. Throughout the process, the researchers came to the ESRF’s macromolecular crystallography beamline ID23-1 to collect high-resolution X-ray diffraction data of the Mpro–inhibitor complexes. They were able to visualise how the inhibitor binds within the active site of the protease. “The ESRF has been crucial in this research, from the beginning, when we scanned the candidate compound, to the end, when we saw how the action takes place”, explains Daniel Ritz, senior director of biology at Idorsia.

One of the features of this study is the small number of compounds they needed, thanks to the highly targeted methodology the scientists used.

The ESRF’s role in drug development

The ESRF, and in particular the structural biology beamlines, have been collaborating with pharmaceutical companies in drug development since the early days of the facility. “Today thanks to the improvement in both the instrumentation and the data processing we can study a much wider variety of compounds, including crystals that are significantly smaller in size and with higher mosaicity, while still obtaining data of sufficient quality to be exploited  ”, explains Estelle Mossou, scientist at the ESRF and industrial liaison with industry.

The recent Hit-to-lead optimization methodology is conditional to the structural biology results and can shorten the time it takes from the discovery of a potential compound to its appearance in the shelves by years. “We are in constant collaboration with the ESRF staff to develop the beamline in the right direction so that we can take the best possible data”, explains Joachim Diez, CEO of Expose. The head of the structural biology group at Idorsia, Aengus Mac Sweeney, adds: “The flexibility of the ESRF and Expose staff, and their focus on providing the best X-ray diffraction data, helps us to support our chemists during hit-to-lead optimisation.”

Reference:

Hazemann, J. et al. Journal of Medicinal Chemistry, 2024. DOI: 10.1021/acs.jmedchem.4c02941

Text by Montserrat Capellas Espuny

Top image: Credits: J. Med. Chem. 2025, 68, 8, 8269-8294