Illingworth, Christopher JR and Scott, Paul D and Parkes, Kevin EB and Snell, Christopher R and Campbell, Matthew P and Reynolds, Christopher A (2010) 'Connectivity and binding-site recognition: Applications relevant to drug design.' Journal of Computational Chemistry, 31 (15). pp. 2677-2688. ISSN 0192-8651

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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. © 2010 Wiley Periodicals, Inc.

Item Type:	Article
Uncontrolled Keywords:	connectivity; ligand-binding sites; k-means; docking; allosteric-binding sites; protein-protein interface inhibitors; molecular chaperones; local connectivity
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science and Health Faculty of Science and Health > Life Sciences, School of
SWORD Depositor:	Elements
Depositing User:	Elements
Date Deposited:	07 Oct 2011 14:26
Last Modified:	15 Jan 2022 00:31
URI:	http://repository.essex.ac.uk/id/eprint/933

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