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

Christopher J.R. Illingworth, Paul D. Scott, Kevin E.B. Parkes, Christopher R. Snell, Matthew P. Campbell, Christopher A. Reynolds

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2677-2688
Number of pages12
JournalJournal of Computational Chemistry
Volume31
Issue number15
Early online date8 Sep 2010
DOIs
Publication statusPublished - 30 Nov 2010
Externally publishedYes

Keywords

  • allosteric-binding sites
  • connectivity
  • docking
  • k-means
  • ligand-binding sites
  • local connectivity
  • molecular chaperones
  • protein-protein interface inhibitors

ASJC Scopus subject areas

  • Chemistry(all)
  • Computational Mathematics

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