Context-Based Identification of Protein-Protein Interfaces and “Hot-Spot” Residues

Geppert, Tim; Hoy, Benjamin; Weßler, Silja; Schneider, Gisbert

doi:10.1016/j.chembiol.2011.01.005

Cited by 65 publications

(64 citation statements)

References 51 publications

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“…iPred uses a knowledge-based scoring function on local residue environments to discriminate interface form non-interface residues. [77] Finally, FINDSITE [78] takes a completely different approach and has the additional advantage that it can be used in low-resolution models. From a target sequence, template structures are identified using a threading algorithm.…”

Section: Binding Site Detectionmentioning

confidence: 99%

Identification of Similar Binding Sites to Detect Distant Polypharmacology

Jalencas

Mestres

2013

Molecular Informatics

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The ability of small molecules to interact with multiple proteins is referred to as polypharmacology. This property is often linked to the therapeutic action of drugs but it is known also to be responsible for many of their side effects. Because of its importance, the development of computational methods that can predict drug polypharmacology has become an important line of research that led recently to the identification of many novel targets for known drugs. Nowadays, the majority of these methods are based on measuring the similarity of a query molecule against the hundreds of thousands of molecules for which pharmacological data on thousands of proteins are available in public sources. However, similarity-based methods are inherently biased by the chemical coverage offered by the active molecules present in those public repositories, which limits significantly their capacity to predict interactions with proteins structurally and functionally unrelated to any of the already known targets for drugs. It is in this respect that structure-based methods aiming at identifying similar binding sites may offer an alternative complementary means to ligand-based methods for detecting distant polypharmacology. The different existing approaches to binding site detection, representation, comparison, and fragmentation are reviewed and recent successful applications presented.

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Section: Binding Site Detectionmentioning

confidence: 99%

Identification of Similar Binding Sites to Detect Distant Polypharmacology

Jalencas

Mestres

2013

Molecular Informatics

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“…Here, the normalized interface propensity (NIP) of individual amino acids calculated from docking poses could predict hot spots with a high accuracy without the need to approximate an energy [218]. Recently, Geppert et al presented iPred [219], which predicts protein-protein interfaces and hotspots based on the difference of local intramolecular atom-and residuespecific pair potentials between interface and non-interface residues. In conjunction with the geometry based pocket detection algorithm PocketPicker [120], iPred identified druggable sites in the interface of the unbound structure of interferon IFN-to its receptor IFNAR.…”

Section: Hot Spot Detectionmentioning

confidence: 98%

Modulating Protein-Protein Interactions: From Structural Determinants of Binding to Druggability Prediction to Application

Metz¹,

Ciglia²,

Gohlke³

2012

CPD

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During the last decades, a large amount of evidence has been gathered on the importance of protein-protein interactions in tuning and regulating most important biological processes. Since many of these pathways are deeply involved in diseases, extensive research efforts have been undertaken towards the modulation of protein-protein interactions. At the early stage of this challenge most of the attention was drawn to the drawbacks of such a therapeutic approach. Encouragingly, however, several recent studies provided a proof of concept that protein-protein interactions are actually valuable targets and that they do have a promising therapeutic potential. This review is divided into three sections. In the first section we summarize the general features of protein-protein interfaces, focusing on the characteristics that make them different from classical protein-ligand binding sites, as well as on problematic aspects that hamper the application of classical drug discovery approaches. In the second section, we present how some of the characteristics of protein-protein interactions can be exploited fruitfully in drug design, hence focusing on the druggability of protein-protein interfaces. Methods successfully applied to protein-protein interactions will be introduced, giving special attention to the computational ones. In the third section, three case studies are presented. First, we describe protein-protein interaction modulators targeting HDM2 and the computational methods applied to identify them. Next, we present the retrospective application of the discussed approaches on the well-examined target IL-2. We conclude with a prospective application to the NHR2 protein, a target just recently validated experimentally with the aid of computational methods.

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“…These so-called hot-spot residues (red, Figure 1 a) often overlap with structurally conserved regions and represent a common feature of PPI interfaces. [2, 4]…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

et al. 2015

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Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helices.

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Context-Based Identification of Protein-Protein Interfaces and “Hot-Spot” Residues

Cited by 65 publications

References 51 publications

Identification of Similar Binding Sites to Detect Distant Polypharmacology

Identification of Similar Binding Sites to Detect Distant Polypharmacology

Modulating Protein-Protein Interactions: From Structural Determinants of Binding to Druggability Prediction to Application

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

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