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Structure and reaction based evaluation of synthetic accessibility

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Abstract

De novo design systems provide powerful methods to suggest a set of novel structures with high estimated binding affinity. One deficiency of these methods is that some of the suggested structures could be synthesized only with great difficulty. We devised a scoring method that rapidly evaluates synthetic accessibility of structures based on structural complexity, similarity to available starting materials and assessment of strategic bonds where a structure can be decomposed to obtain simpler fragments. These individual components were combined to an overall score of synthetic accessibility by an additive scheme. The weights of the scoring function components were calculated by linear regression analysis based on accessibility scores derived from medicinal chemists. The calculated values for synthetic accessibility agree with the values proposed by chemists to an extent that compares well with how chemists agree with each other.

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Acknowledgments

The authors would like to thank the medicinal chemists of our pharmaceutical partner companies (4SC, Altana, Lilly) for evaluating the synthetic accessibility of our dataset. We are also grateful to Elsevier MDL for making available the Theilheimer reaction database for us. We are also grateful to our partners at BioSolveIT and the Center for Bioinformatics (ZBH) of the University of Hamburg for their contributions. Finally, we would like to acknowledge the work and support of the MOSES development team, especially the contribution of Achim Herwig and Oliver Sacher. This work has been financed by the German Federal Ministry of Education and Research (BMBF) as part of the NovoBench project (Project number: 0313324A).

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Author notes

  1. Thomas Seidel

    Present address: Institut für Angewandte Synthesechemie, Technische Universität Wien, A 1060, Vienna, Austria

Authors and Affiliations

  1. Computer-Chemie-Centrum, Universität Erlangen-Nürnberg, D 91052, Erlangen, Germany

    Krisztina Boda, Thomas Seidel & Johann Gasteiger

Authors
  1. Krisztina Boda
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  2. Thomas Seidel
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  3. Johann Gasteiger
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Correspondence to Johann Gasteiger.

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Boda, K., Seidel, T. & Gasteiger, J. Structure and reaction based evaluation of synthetic accessibility. J Comput Aided Mol Des 21, 311–325 (2007). https://doi.org/10.1007/s10822-006-9099-2

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  • DOI: https://doi.org/10.1007/s10822-006-9099-2

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