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ParaFrag—an approach for surface-based similarity comparison of molecular fragments

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Abstract

A frequent task in computer-aided drug design is to identify novel chemotypes similar in activity but structurally different to a given reference structure. Here we report the development of a novel method for atom-independent similarity comparison of molecular fragments (substructures of drug-like molecules). The fragments are characterized by their local surface properties coded in the form of 3D pharmacophores. As surface properties, we used the electrostatic potential (MEP), the local ionization energy (IEL), local electron affinity (EAL) and local polarizability (POL) calculated on isodensity surfaces. A molecular fragment can then be represented by a minimal set of extremes for each surface property. We defined a tolerance sphere for each of these extremes, thus allowing us to assess the similarity of fragments in an analogous manner to classical pharmacophore comparison. As a first application of this method we focused on comparing rigid fragments suitable for scaffold hopping. A retrospective analysis of successful scaffold hopping reported for Factor Xa inhibitors [Wood MR et al (2006) J Med Chem 49:1231] showed that our method performs well where atom-based similarity metrics fail.

Encoding surface hotspots as a ParaFrag pharmacophore

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Acknowledgments

We thank David Whitley and Brian Hudson, Center for Molecular Design, University of Portsmouth, UK for helpful discussions and for providing the results of the spherical harmonics calculation. This work would not have been possible without support of our colleagues in the Cheminformatics & Molecular Modeling group at Roche, Basel. In particular we thank Wolfgang Guba, Daniel Stoffler, Olivier Roche and Martin Stahl. We thank Wolfram Altenhofen and Guido Kirsten, Chemical Computing Group, for providing an interface for visualizing the local property surfaces in MOE.

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Authors and Affiliations

  1. Discovery Chemistry, F. Hoffmann–La Roche AG, 4070, Basel, Switzerland

    Arjen-Joachim Jakobi & Harald Mauser

  2. Computer Chemie Centrum and Interdisciplary Center for Molecular Materials, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstrasse 25, 91052, Erlangen, Germany

    Arjen-Joachim Jakobi & Timothy Clark

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  1. Arjen-Joachim Jakobi
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  2. Harald Mauser
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Correspondence to Harald Mauser.

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Jakobi, AJ., Mauser, H. & Clark, T. ParaFrag—an approach for surface-based similarity comparison of molecular fragments. J Mol Model 14, 547–558 (2008). https://doi.org/10.1007/s00894-008-0302-3

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