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ReCore: example 3: Adenosine Deaminase

Applying ReCore to the concept of Fragment Merging

In the original paper [1], the authors state: Simple linking would not have worked in this case, as the individually bound fragments (68 and 69) cause conformational changes in the protein upon binding that would have hindered a simple linking approach. Reengineering the original fragments preserved their binding contacts responsible for potency and produced vectors for merging.

ReCore yields almost the same scaffold of the merged molecule as in the original publication. The compound resulted in a dramatically improved potency.
ReCore yielded the scaffold replacement within seconds only.

Using your corporate compounds as a starting point for a fragment library, your possibility of replacements would grow dramatically.

  PDB: 1ndv 2e1w  
    The cutting points are defined by the exit vectors shown in green.
Here are the results:
  Rank: 5 6 12
  DUD: ZINC03431169 ZINC00616467 ZINC00634089
[1]Erlanson, D.A. et al., . J. Med. Chem. 2004, 47, 3463 ff.