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Cryptic binding sites on proteins: definition, detection, and druggability.

Authors
  • Vajda, Sandor1
  • Beglov, Dmitri2
  • Wakefield, Amanda E3
  • Egbert, Megan2
  • Whitty, Adrian4
  • 1 Department of Biomedical Engineering, Boston University, Boston, MA 02215, United States; Department of Chemistry, Boston University, Boston, MA 02215, United States. Electronic address: [email protected] , (United States)
  • 2 Department of Biomedical Engineering, Boston University, Boston, MA 02215, United States. , (United States)
  • 3 Department of Biomedical Engineering, Boston University, Boston, MA 02215, United States; Department of Chemistry, Boston University, Boston, MA 02215, United States. , (United States)
  • 4 Department of Chemistry, Boston University, Boston, MA 02215, United States. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Current opinion in chemical biology
Publication Date
Jun 01, 2018
Volume
44
Pages
1–8
Identifiers
DOI: 10.1016/j.cbpa.2018.05.003
PMID: 29800865
Source
Medline
Language
English
License
Unknown

Abstract

Many proteins in their unbound structures lack surface pockets appropriately sized for drug binding. Hence, a variety of experimental and computational tools have been developed for the identification of cryptic sites that are not evident in the unbound protein but form upon ligand binding, and can provide tractable drug target sites. The goal of this review is to discuss the definition, detection, and druggability of such sites, and their potential value for drug discovery. Novel methods based on molecular dynamics simulations are particularly promising and yield a large number of transient pockets, but it has been shown that only a minority of such sites are generally capable of binding ligands with substantial affinity. Based on recent studies, current methodology can be improved by combining molecular dynamics with fragment docking and machine learning approaches. Copyright © 2018 Elsevier Ltd. All rights reserved.

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