Fig. 3

Retrospective Comparison of crystallised and placed derivative ligand from NUDT7 study A and tubulin B study, illustrating a merger with hits that do not overlap cleanly and a merger requiring a user-defined mapping respectively. In the NUDT7 study, the two fragment hits PCM0102716 (1, coral, LHS) and NU181 (2, in lavender, LHS) were merged by Resnick et al. yielding the merger NU443 (3) [34]. The crystal structure of 3a (turquoise, RHS) overlayed with the placement predicted by Fragmenstein (green, RHS). 2 and 3a are covalently bound with Cys73 via an warhead. Internally outside of the PyRosetta operations, covalent attachment atoms are stored as dummy/R/* atoms, shown in white.In the tubulin study (pane B), F04 (4, lavender) and F36 (5, coral) inspired Todalam-4 (6, sky-blue: crystal, green: predicted). The aminothiazole ring is flipped between 5 and 6 by design. A constructive observation of this derivative is that the N-benzyl is rotated in the crystal relative to 4 possibly to attain a T-shaped pi bond, a dipole-momentum–driven configuration, which is not modelled in classical mechanics forcefields such as that employed by Rosetta