Science Pool

Originally presented in Science Translational Medicine, this article co-written with Merck & Co. presents a set of bifunctional HIV therapies, dubbed targeted activator of cell kill (TACK) molecules, that were optimized for simultaneous antiviral activity and selective elimination of infected CD4+ T cells from HIV-1 patients.

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Variants of isocitrate dehydrogenase IDH 1 and 2 are known to alter the metabolism in cancer cells. Through a combined approach of X-ray crystallography and 1H NMR in collaboration with Christopher Schofield from University of Oxford, we reveal that 2OG derivatives can serve as substrates of the investigated IDH1/2 variants, but not of WT IDH1/2, and have the potential to act as 2OG-competitive inhibitors.

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Thermostability assays (DSF) are one of the workhorses of biochemistry and structural biology. Thanks to the simplicity of the assay setup they found wide applications in many fields. To meet the high demand in DSF assays from our clients, Evotec established DSF pipelines in all five of the sites that offer biophysics services. We find that thermostability assays are highly useful for hit validation & expansion, however, can be also used to reveal the mode of action of the candidate molecule.

In this presentation we:

• Describe how we use thermal unfolding assays (DSF) to support drug discovery
• Discuss the cases when model-based analysis reveals in-depth information about the drug/target interaction
• Share the perspectives on combing high-throughput and high-content approaches

The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and there is great interest in developing SARM1 enzyme inhibitors as candidate therapies for multiple neurodegenerative diseases.

Through a combined approach of X-ray crystallography and cryo-EM we uncovered the molecular mechanism of SARM1 inhibition by a compound (DSRM-3716), demonstrating that it undergoes a base-exchange reaction with the nicotinamide moiety of NAD+, and that the transferase product is the bona fide inhibitor. Further more we reveal the activated state of SARM1 for the first time.

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Watch the webinar to learn more about exciting new developments in predictive toxicology!

About the Webinar

In this webinar, John Barker, SVP Global Head of Protein Sciences discusses bacterial infections and global health within anti-infectives. John gave this talk at the Oxford Global Discovery UK event in October 2021.

About the Speaker

John Barker, PhD FRSB Senior Vice President, Global Head of Protein Sciences | Evotec Currently responsible for more than 150 scientists across four sites, Princeton NJ, Abingdon UK, Toulouse and Hamburg. Team delivering Protein Production, Structural Biology and Cellular Sciences both internally and to Evotec’s partnerships. Over the past 18 years built from the ground up the current Evotec structural biology unit, now with more than 30 PhD scientists, one of the largest units in industry. Supporter of UK industry as the Industrial Life Science representative on the Diamond Scientific Advisory Board. John has worked on more than 40 collaborations across a range of drug discovery projects including multiple structure and fragment guided programmes in all therapeutic areas.

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In this article, we discuss the role of structure-based virtual screening in drug discovery. 

The publication covers:

• an overview of structural-based virtual screening and the importance of selecting the most appropriate protocol for affinity estimation calculations
• the development of an automated calibration process implemented in a Knime workflow consisting of 4 steps:
  • preparation of a protein test set with structures and models of the target
  • preparation of a compound test set with target-related ligands and decoys
  • automatic test of 24 scoring/rescoring protocols for each target structure and model
  • graphical display of the results
•  demonstration of the application of this tool in setting up an optimal protocol for structure-based virtual screening against Retinoid X Receptor alpha

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