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The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors

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Abstract

We have determined the effects that tightly bound water molecules have on the de novo design of cyclin-dependent kinase-2 (CDK2) ligands. In particular, we have analyzed the impact of a specific structural water molecule on the chemical diversity and binding mode of ligands generated through a de novo structure-based ligand generation method in the binding site of CDK2. The tightly bound water molecule modifies the size and shape of the binding site and we have found that it also imposed constraints on the observed binding modes of the generated ligands. This in turn had the indirect effect of reducing the chemical diversity of the underlying molecular scaffolds that were able to bind to the enzyme satisfactorily.

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Acknowledgements

ATGS is grateful to Consejo Nacional de Ciencia y Tecnología (CoNaCyT, México) for the award of a post-graduate scholarship and to the Universities UK for an Overseas Research Scheme award. The authors would like to thank Dr. Nikolay P. Todorov, Dr. Stuart Firth-Clark and Dr. Christoph Buenemann for helpful and fruitful discussions.

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Author notes

  1. Alfonso T. García-Sosa

    Present address: Computer-Aided Molecular Design Laboratory, Guggenheim 711, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA

Authors and Affiliations

  1. Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK

    Alfonso T. García-Sosa

  2. Western Australian Biomedical Research Institute, School of Biomedical Sciences and School of Pharmacy, Curtin University of Technology, G.P.O. Box U1987, Perth, WA, 6865, Australia

    Ricardo L. Mancera

Authors
  1. Alfonso T. García-Sosa
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  2. Ricardo L. Mancera
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Correspondence to Alfonso T. García-Sosa or Ricardo L. Mancera.

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García-Sosa, A.T., Mancera, R.L. The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors. J Mol Model 12, 422–431 (2006). https://doi.org/10.1007/s00894-005-0063-1

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  • DOI: https://doi.org/10.1007/s00894-005-0063-1

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