Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics

PLoS One. 2016 Apr 28;11(4):e0154046. doi: 10.1371/journal.pone.0154046. eCollection 2016.


Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer-Aided Design
  • Drug Design*
  • Humans
  • Interleukin-10 / chemistry
  • Interleukin-10 / metabolism*
  • Interleukin-10 Receptor alpha Subunit / chemistry
  • Interleukin-10 Receptor alpha Subunit / metabolism*
  • Ligands
  • Models, Molecular
  • Peptidomimetics / chemistry*
  • Peptidomimetics / pharmacology*
  • Protein Binding / drug effects
  • Protein Conformation


  • Interleukin-10 Receptor alpha Subunit
  • Ligands
  • Peptidomimetics
  • Interleukin-10

Grant support

GRG thanks the Alexander von Humboldt Foundation for a postdoctoral fellowship. The authors acknowledge support by the German Research Foundation and the Open Access Publication Funds of the TU Dresden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.