Journal of Molecular Modeling

, Volume 12, Issue 4, pp 422–431

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

Original paper

DOI: 10.1007/s00894-005-0063-1

Cite this article as:
García-Sosa, A.T. & Mancera, R.L. J Mol Model (2006) 12: 422. doi:10.1007/s00894-005-0063-1

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.

Keywords

Hydration Solvation Structure-based drug design CDK2 

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of CambridgeCambridgeUK
  2. 2.Western Australian Biomedical Research Institute, School of Biomedical Sciences and School of PharmacyCurtin University of TechnologyPerthAustralia
  3. 3.Computer-Aided Molecular Design Laboratory, Guggenheim 711Mayo Clinic College of MedicineRochesterUSA

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