Fig. 2: Fragment expansion in synthetically accessible chemical space.
From: Virtual fragment screening for DNA repair inhibitors in vast chemical space
a Docking of commercial chemical libraries containing 14 million (14 M) fragments led to identification of fragment 1, a weak OGG1 inhibitor. b Crystal structures of mouse OGG1 bound to inhibitors enabled increasingly complex chemical pattern searches in commercial make-on-demand libraries. By stepwise increasing the size of the fragment, compounds 5 and 7 (IC50 = 58 and 6.6 μM, respectively) were discovered and crystal structures of these were determined (PDB accession codes: 7Z5R and 7ZC7). c Suitable building blocks were retrieved using pattern matching based on the molecular topology of compound 7. A tailored virtual chemical library was constructed based on several coupling reactions, yielding 6720 products. Docking then guided selection of compounds from the virtual library, which were synthesized in-house and led to the discovery of compounds 17 and 23 (IC50 = 600 nM, Table 1). A crystal structure of mouse OGG1 in complex with compound 17 (PDB accession code: 7Z5B) confirmed the computationally designed hydrogen bond to Asp322. Structure-guided elaboration leading to compounds 17 and 23 resulted in a > 165-fold increase of inhibitory potency compared to fragment 1. Source data are provided as a Source Data file.
