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

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

Author information

1
Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg, Dresden, Germany.
2
Helmholtz-Zentrum Dresden Rossendorf, Institute of Resource Ecology, Dresden, Germany.
3
Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
4
Helmholtz-Zentrum Dresden Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.

Abstract

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.

PMID:
27123592
PMCID:
PMC4849758
DOI:
10.1371/journal.pone.0154046
[Indexed for MEDLINE]
Free PMC Article

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