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.
Highlights
Protein-protein interactions (PPIs) mediate most biological processes and, represent relevant avenues as targets for the development of therapeutics
As strategy to ease the definition of key functionalities in the targeted binding site, we downsized the number of residues to be taken into account by a selection procedure based on: i) calculated residue binding energy contribution, ii) interfacial hydrogen bond network with IL-10, and iii) proximity in space
Though downsizing the large binding epitope to three residues would imply at first none or considerably low binding affinity of any seeding template molecule containing them, the geometric and functional constraints demarcated by the side chains of the selected residues would constitute the minimal 3D functional descriptors to generate regular expressions signifying relevant functionalities of the targeted recognition site to be mimicked (Fig 1)
Summary
Protein-protein interactions (PPIs) mediate most biological processes and, represent relevant avenues as targets for the development of therapeutics. In most cases, the large size, the discontinuous nature, and even the lack of well-defined secondary structure of protein-protein interfaces [12,13,14] do not allow a straightforward transfer of such relevant residues directly into a small scaffold with high affinity to the targeted recognition site [2, 4]. Antibodies are suboptimal as drugs mainly due to their low oral bioavailability and cell permeability, slow pharmacokinetics and, sometimes, insufficient stability From this perspective, small molecules, which can be engineered to target every potential protein of interest, are advantageous over biomacromolecules. Small chemical scaffolds such as triazacyclophane have been used to covalently attach discontinuous binding epitopes without further spatial arrangement considerations [20, 21]
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