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CONFIRM: connecting fragments found in receptor molecules

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Abstract

A novel algorithm for the connecting of fragment molecules is presented and validated for a number of test systems. Within the CONFIRM (Connecting Fragments Found in Receptor Molecules) approach a pre-prepared library of bridges is searched to extract those which match a search criterion derived from known experimental or computational binding information about fragment molecules within a target binding site. The resulting bridge ‘hits’ are then connected, in an automated fashion, to the fragments and docked into the target receptor. Docking poses are assessed in terms of root-mean-squared deviation from the known positions of the fragment molecules, as well as docking score should known inhibitors be available. The creation of the bridge library, the full details and novelty of the CONFIRM algorithm, and the general applicability of this approach within the field of fragment-based de novo drug design are discussed.

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Notes

  1. We have used an OEChem utility for computing the RMSD.

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Acknowledgement

We would like to thank J. Christian Baber for fruitful discussions during the preparation of this manuscript.

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Authors and Affiliations

  1. Wyeth Research, Chemical and Screening Sciences, 200 CambridgePark Drive, Cambridge, MA, 02140, USA

    David C. Thompson, R. Aldrin Denny, Ramaswamy Nilakantan, Diane Joseph-McCarthy & Eric Feyfant

  2. Wyeth Research, Chemical and Screening Sciences, 865 Ridge Road, Princeton, NJ, 08543, USA

    Christine Humblet

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  1. David C. Thompson
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Correspondence to Eric Feyfant.

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Thompson, D.C., Aldrin Denny, R., Nilakantan, R. et al. CONFIRM: connecting fragments found in receptor molecules. J Comput Aided Mol Des 22, 761–772 (2008). https://doi.org/10.1007/s10822-008-9221-8

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  • DOI: https://doi.org/10.1007/s10822-008-9221-8

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