Excited to be at VU Amsterdam to listen to the Nauta Lecture of György Keserű on "Covalent fragment approaches in drug discovery". He gave a great overview of his group`s many groundbreaking contributions to tool development for #DrugDiscovery and his newest work on photoactivatable fragments.(1/7) - ThreadSky

stephanhacker2.bsky.social • 12 days ago

Excited to be at VU Amsterdam to listen to the Nauta Lecture of György Keserű on "Covalent fragment approaches in drug discovery". He gave a great overview of his group`s many groundbreaking contributions to tool development for #DrugDiscovery and his newest work on photoactivatable fragments.(1/7)

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stephanhacker2.bsky.social•12 days ago

He started by giving a very clear overview of the concept of #CovalentInhibitors and the important advantages that they can have in #DrugDiscovery. He especially highlighted, how powerful covalent fragments can be in this context. (2/7) https://www.sciencedirect.com/science/article/pii/S0165614723001840?via%3Dihub

stephanhacker2.bsky.social•12 days ago

Next, he talked about his group's SpotXplorer approach to design fragment libraries containing diverse pharmacophores that are priviliged to bind to ligand-binding hot spots in proteins. (3/7) https://www.nature.com/articles/s41467-021-23443-y?utm_campaign=related_content&utm_source=HEALTH&utm_medium=communities

stephanhacker2.bsky.social•12 days ago

He then focussed in on "conditional covalent chemistry" using molecules that can be photoactivated into covalent binders. For this purpose, they equipped their fragment libraries with diazirine-based photocrosslinkers to achieve light-dependent covalent labeling. (4/7) https://www.nature.com/articles/s42004-024-01252-w

stephanhacker2.bsky.social•12 days ago

In collaboration with @jtbush.bsky.social of GSK, they used these libraries (PhaBits) to detect binding to proteins using intact protein mass spectrometry on the examples of BRD4, KRAS G12D and STAT5B. (5/7) https://www.nature.com/articles/s42004-024-01252-w

stephanhacker2.bsky.social•12 days ago

Interesting thoughts that the pharmacophore-based fragment library leads to less oversampling of prominent binding sites and also allows the identification of ligands for multiple, also less druggable, binding sites on the protein, if they exist. (6/7)

stephanhacker2.bsky.social•12 days ago

Finally, he talked about the use of photofoldamers based on β-amino acids and photocrosslinkers to address protein-protein interactions. Interesting insights into linking two foldamer hits in order to improve potency. (7/7) https://onlinelibrary.wiley.com/doi/10.1002/anie.202410435

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