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A new method for estimating the importance of hydrogen-bonding groups in the binding site of a protein

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Abstract

We introduce a new method to estimate the importance of hydrogen-bonding sitepoints in the binding site of a protein as part of a structure-based design strategy. Our method identifies hydrogen-bonding sitepoints within a binding pocket and ranks them according to both the accessibility of their hydrogen bonding regions to incoming ligands and their hydrogen-bonding strength. The combination of these components produces a prioritised list of sitepoints that are more likely to be involved in hydrogen bonding with an incoming ligand. A dataset of known protein-ligand interactions was used to compare the prioritisation of sitepoints identified by our method with those observed to be engaged in hydrogen bonding in their crystal structures. Our method was able to remove those sitepoints unable to bind the ligand due to a low accessibility or an unfavourable orientation and to award significantly higher hydrogen-bonding ranking values to those sitepoints observed to form hydrogen bonds. Our method can thus be used to identify hydrogen-bonding sitepoints that should be targeted preferentially in a drug design strategy.

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Authors and Affiliations

  1. Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QJ, United Kingdom

    Matthew D. Kelly

  2. De Novo Pharmaceuticals, Compass House, Vision Park, Chivers Way, Histon, Cambridge, CB4 9ZR, United Kingdom

    Ricardo L. Mancera

Authors
  1. Matthew D. Kelly
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  2. Ricardo L. Mancera
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Kelly, M.D., Mancera, R.L. A new method for estimating the importance of hydrogen-bonding groups in the binding site of a protein. J Comput Aided Mol Des 17, 401–414 (2003). https://doi.org/10.1023/A:1027346709963

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