Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics
Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung
Beitragende
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.
Details
Originalsprache | Englisch |
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Aufsatznummer | e0154046 |
Seitenumfang | 25 |
Fachzeitschrift | PloS one |
Jahrgang | 11 |
Ausgabenummer | 4 |
Publikationsstatus | Veröffentlicht - 2016 |
Peer-Review-Status | Ja |
Externe IDs
PubMedCentral | PMC4849758 |
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Scopus | 85015333462 |
Schlagworte
Schlagwörter
- Binding Sites, Computer-Aided Design, Drug Design, Humans, Interleukin-10/chemistry, Interleukin-10 Receptor alpha Subunit/chemistry, Ligands, Models, Molecular, Peptidomimetics/chemistry, Protein Binding/drug effects, Protein Conformation