Fig. 4: Case study for fragment-based design of IMPDH inhibitors.
From: Equivariant 3D-conditional diffusion model for molecular linker design
a, Experimentally identified fragment hits by ref. 6 (PDB code 5OU2), with IMPDH shown in blue. b, Starting fragments after removing bromine. c, Crystal structure of the most potent inhibitor (compound 31) reported in ref. 6 (PDB code 5OU3). d, DiffLinker sample that reproduces compound 31. e, DiffLinker sample that reproduces compound 30. f, Chemical structures of three potent inhibitors reported in ref. 6. g, Three DiffLinker samples with highest chemical similarity (Tanimoto distance) to compound 29. h, Distribution of GNINA scores for unique samples (n = 800) generated by DiffLinker. Red solid line depicts the score of experimentally validated compound 31. Blue dashed lines represent scores for eight DiffLinker samples that recover compound 31. On the right, we represent the interactions between a molecule (top, reference; bottom, DiffLinker sample with the highest score) and the target IMPDH pocket computed by PLIP22.
