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A validation study on the practical use of automated de novo design

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Abstract

The de novo design program Skelgen has been used to design inhibitor structures for four targets of pharmaceutical interest. The designed structures are compared to modeled binding modes of known inhibitors (i) visually and (ii) by means of a novel similarity measure considering the size and spatial proximity of the maximum common substructure of two small molecules. It is shown that the Skelgen algorithm generates representatives of many inhibitor classes within a very short time and that the new similarity measure is useful for comparing and clustering designed structures. The results demonstrate the necessity of properly defining search constraints in practical applications of de novo design.

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Authors and Affiliations

  1. F.Hoffmann-La Roche Ltd, Basel, Switzerland

    Martin Stahl, Harald Mauser & Hans-Joachim Boehm

  2. De Novo Pharmaceuticals Ltd, Compass House, Vision Park, Histon, Cambridge CB49ZR, UK

    Nikolay P. Todorov, Tim James & Philip M. Dean

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  1. Martin Stahl
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Stahl, M., Todorov, N.P., James, T. et al. A validation study on the practical use of automated de novo design. J Comput Aided Mol Des 16, 459–478 (2002). https://doi.org/10.1023/A:1021242018286

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