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

J Chem Inf Model. 2015 Aug 24;55(8):1585-99. doi: 10.1021/acs.jcim.5b00103. Epub 2015 Aug 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites / drug effects
  • Databases, Protein
  • Drug Discovery / methods*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Targeted Therapy
  • Protein Binding
  • Protein Interaction Domains and Motifs / drug effects
  • Protein Interaction Mapping / methods*
  • Protein Interaction Maps / drug effects*
  • Proteins / chemistry
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Ligands
  • Proteins
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2