Drug development is hard, arguably one of the most complex processes existing. For every drug that gets approved in the end, 10,000 molecules need to be designed, made and tested. The ’easy’ targets have already been addressed, so there is no low-hanging fruit anymore. Furthermore the synthetically accessible space is increasing at an enormous pace, which makes it technically challenging to select relevant molecules to start a project. Fragment-based drug discovery has evolved as an efficient strategy to generate tractable starting points for lead generation, and has so far delivered 6 approved drugs, with many being progressed in ongoing clinical trials. In collaboration with Jens Carlsson at Uppsala University, and Pål Stenmark at Stockholm University, we have combined in silico fragment screening of millions of fragments with x-ray crystallography to identify novel inhibitors for the DNA repair enzyme OGG1, a difficult-to-drug target. Subsequent fragment elaboration using searches among billions of readily synthesizable compounds yielded submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells.

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