AlphaSpace: Fragment-Centric Topographical Mapping to Target Protein-Protein Interaction Interfaces

David Rooklin, Cheng Wang, Joseph Katigbak, Paramjit S. Arora, Yingkai Zhang

Research output: Contribution to journalArticlepeer-review


Inhibition of protein-protein interactions (PPIs) is emerging as a promising therapeutic strategy despite the difficulty in targeting such interfaces with drug-like small molecules. PPIs generally feature large and flat binding surfaces as compared to typical drug targets. These features pose a challenge for structural characterization of the surface using geometry-based pocket-detection methods. An attractive mapping strategy - that builds on the principles of fragment-based drug discovery (FBDD) - is to detect the fragment-centric modularity at the protein surface and then characterize the large PPI interface as a set of localized, fragment-targetable interaction regions. Here, we introduce AlphaSpace, a computational analysis tool designed for fragment-centric topographical mapping (FCTM) of PPI interfaces. Our approach uses the alpha sphere construct, a geometric feature of a protein's Voronoi diagram, to map out concave interaction space at the protein surface. We introduce two new features - alpha-atom and alpha-space - and the concept of the alpha-atom/alpha-space pair to rank pockets for fragment-targetability and to facilitate the evaluation of pocket/fragment complementarity. The resulting high-resolution interfacial map of targetable pocket space can be used to guide the rational design and optimization of small molecule or biomimetic PPI inhibitors.

Original languageEnglish (US)
Pages (from-to)1585-1599
Number of pages15
JournalJournal of Chemical Information and Modeling
Issue number8
StatePublished - Aug 24 2015

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering
  • Computer Science Applications
  • Library and Information Sciences


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