Structure-based inhibition of protein-protein interactions

Andrew M. Watkins, Paramjit S. Arora

Research output: Contribution to journalArticlepeer-review

Abstract

Protein-protein interactions (PPIs) are emerging as attractive targets for drug design because of their central role in directing normal and aberrant cellular functions. These interactions were once considered gundruggableg because their large and dynamic interfaces make small molecule inhibitor design challenging. However, landmark advances in computational analysis, fragment screening and molecular design have enabled development of a host of promising strategies to address the fundamental molecular recognition challenge. An attractive approach for targeting PPIs involves mimicry of protein domains that are critical for complex formation. This approach recognizes that protein subdomains or protein secondary structures are often present at interfaces and serve as organized scaffolds for the presentation of side chain groups that engage the partner protein(s). Design of protein domain mimetics is in principle rather straightforward but is enabled by a host of computational strategies that provide predictions of important residues that should be mimicked. Herein we describe a workflow proceeding from interaction network analysis, to modeling a complex structure, to identifying a high-affinity sub-structure, to developing interaction inhibitors. We apply the design procedure to peptidomimetic inhibitors of Ras-mediated signaling.

Original languageEnglish (US)
Pages (from-to)480-488
Number of pages9
JournalEuropean journal of medicinal chemistry
Volume94
DOIs
StatePublished - Apr 13 2015

Keywords

  • Computational tools
  • Inhibitor design
  • Peptidomimetic
  • Protein structure
  • Protein-protein interaction

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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