Connectivity and binding-site recognition: applications relevant to drug design

Illingworth, C. J.R. , Scott, P. D., Parkes, K. E. B., Snell, C. R., Campbell, M. P. and Reynolds, C. A. (2010) Connectivity and binding-site recognition: applications relevant to drug design. Journal of Computational Chemistry, 31(15), pp. 2677-2688. (doi: 10.1002/jcc.21561) (PMID:20839295)

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Abstract

Here, we describe a family of methods based on residue–residue connectivity for characterizing binding sites and apply variants of the method to various types of protein–ligand complexes including proteases, allosteric-binding sites, correctly and incorrectly docked poses, and inhibitors of protein–protein interactions. Residues within ligand-binding sites have about 25% more contact neighbors than surface residues in general; high-connectivity residues are found in contact with the ligand in 84% of all complexes studied. In addition, a k-means algorithm was developed that may be useful for identifying potential binding sites with no obvious geometric or connectivity features. The analysis was primarily carried out on 61 protein–ligand structures from the MEROPS protease database, 250 protein–ligand structures from the PDBSelect (25%), and 30 protein–protein complexes. Analysis of four proteases with crystal structures for multiple bound ligands has shown that residues with high connectivity tend to have less variable side-chain conformation. The relevance to drug design is discussed in terms of identifying allosteric-binding sites, distinguishing between alternative docked poses and designing protein interface inhibitors. Taken together, this data indicate that residue–residue connectivity is highly relevant to medicinal chemistry.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Illingworth, Dr Chris
Authors: Illingworth, C. J.R., Scott, P. D., Parkes, K. E. B., Snell, C. R., Campbell, M. P., and Reynolds, C. A.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Journal of Computational Chemistry
Publisher:Wiley
ISSN:0192-8651
ISSN (Online):1096-987X
Published Online:08 September 2010

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