ReCore

3D Scaffold Hopping. Guaranteed.

advantages

  • Replace central elements in known bioactive molecules
  • Generate new scaffolds in 3D in the blink of an eye
  • Impose pharmacophore constraints interactively
  • Custom design your own fragment database for scaffold replacement

testimonials

  • In my opinion, software of this sort belongs on the desktop of any chemist designing bioactive molecules.
    John van Drie in JACS 131 (2009) 1617
  • ReCore works well! It has a user-friendly interface, and the constraints are easy to set up.
    GSK, China.
  • The diversity of solutions from ReCore is much better than similar types of software.
    Roberto Forlani, NiKem Research Srl, Italy.
  • ReCore proposed an elegant ring closure in a linear scaffold, not only retaining key pharmacophore features, but activity as well.
    Sander Nabuurs, LeadPharma, The Netherlands.

scientific background

  • ReCore replaces a given core: Given a pre-defined central unit of a molecule (the core), fragments are searched in a 3D database for the best possible replacement – whilst keeping all connected residues, i.e., the rest of the query compound in place. Additionally, user-defined "pharmacophore" constraints can be employed to restrict solutions.
  • A typical workflow is a two stage process, of which Stage A needs to be performed only once (click picture for further information).
  • For more details please see the original publication:

    Maass, P.; Schulz-Gasch, T.; Stahl, M.; Rarey, M; ReCore: A Fast and Versatile Method for Scaffold Hopping Based on Small Molecule Crystal Structure Conformations. J. Chem. Inf. Model. 2007

application scenarios

"Sounds great, however, does it work?" – Works a treat, see for yourself, here are some examples:

HIV Reverse Transcriptase – are results similar to known inhibitors?

Here is CSD MSC194 with the two green bonds defining the query "exit vectors":
         
Here are results (yellow), overlaid with the query:
   
  Rank: 4 1 125  
  CSD: MOZJUG CABVAD XUCPUG  
  PDB analog: 1eet 1s9e 1ddt  
Here are closely related inhibitors (in orange) superimposed with the ReCore solutions:
     
  PDB: 1eet 1s9e 1ddt  
  Note: amide flip suggestion meta substituted aromatics a close match to a Trovirdine derivative  

TRH (Thyrotropin Releasing Hormone) – how does ReCore deal with 3 cutting points?

A typical ReCore query was taken from a TRH CSD crystal (TRHTRT) and torsionally modified to satisfy Olson's [1] idea (cp. below). To obtain more rigid results, a "pharmacophore" priority was introduced: A ring atom has to lie within the sphere depicted in red.
       
Based on the query (please note the green arrows), ReCore generates several interesting and nicely aligning cyclic structures; here are the ReCore results (colored) with the query in grey:
   
  Rank: 12 5 6 7
  CSD: HUWHEM KIFZAA SUMVEB TCHXET
  Note: saturated ring aromatic ring rings are good a tri-subst'd 6-ring
And, actually, the tri-substituted 6-ring was the basis for a TRH peptide mimetic by Olson [1] (in orange):
         
[1]Olson et al., . J. Med. Chem. 1995, 38, 2866-2879.

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.

We have seen similar results for other targets! For more application examples please see the original publication.

credits

ReCore has been developed by Patrick Maass in Matthias Rarey's group at the ZBH, University of Hamburg, in collaboration with F. Hoffmann-La Roche AG (Basel, Switzerland).

The graphics were made available by courtesy of Martin Stahl and Tanja Schulz-Gasch at F. Hoffmann-La Roche.

indices

ReCore requires a 3D fragment library to search in. Depending on the tool you want to use, please proceed with:

SeeSAR-ReCore indices
LeadIT-ReCore indices

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