Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics.
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.
Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg, Dresden, Germany.
Gloria
G
Ruiz-Gómez
Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg, Dresden, Germany.
John C
JC
Hawkins
Helmholtz-Zentrum Dresden Rossendorf, Institute of Resource Ecology, Dresden, Germany.
Jenny
J
Philipp
Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
Georg
G
Künze
Helmholtz-Zentrum Dresden Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
Robert
R
Wodtke
Helmholtz-Zentrum Dresden Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
Reik
R
Löser
Helmholtz-Zentrum Dresden Rossendorf, Institute of Resource Ecology, Dresden, Germany.
Karim
K
Fahmy
Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg, Dresden, Germany.
M Teresa
MT
Pisabarro
D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D016753:Interleukin-10 / Q000737:chemistry / Q000378:metabolism*; D053709:Interleukin-10 Receptor alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation
D053709:Interleukin-10 Receptor alpha Subunit; D008024:Ligands; D057786:Peptidomimetics; D016753:Interleukin-10