Inhibition of protein–protein interactions using designed molecules

Abstract

Although many cellular processes depend upon enzymatic reactions, protein-protein interactions (PPIs) mediate a large number of important regulatory pathways and thus play a central role in disease development. In order to understand and selectively inhibit cellular signalling pathways, there is a pressing need for small molecules that target PPIs, particularly in the context of pharmaceutical development. This tutorial review will introduce the relevance of PPIs to chemical biology and highlight the key challenges in designing inhibitors. Some of the successes using conventional approaches to the identification of small-molecule PPI inhibitors will be highlighted, and also the reasons why these approaches have not always proven successful. Several general approaches tailored to particular protein topologies are emerging for the design of scaffolds that inhibit PPIs-these will form the major content of this review. Finally a summary of the challenges to be faced in developing inhibitors of PPIs into drug leads and how these challenges may differ from those encountered with enzyme-like targets will be given.

Protein/peptide secondary structural mimics: design, characterization, and modulation of protein–protein interactions

“…155 The possibilities of structural design for the purpose of mimicking are theoretically unlimited, and thus molecular designs could number far more than those discussed above. 156 Interestingly, small molecules can also serve as helix mimics, such as the 2,6,9-tri-substituted purine introduced by Fletcher et al 157 At the same time, the combination of physical chemistry analysis and chemical design can predict better mimetic structures. 158 If we think out of the box, these helices can be regarded as incomplete and unstable barrels with hollow chambers.…”

Generation of Dynamic Combinatorial Libraries Using Hydrazone‐Functionalized Surface Mimetics

“…A central goal in supramolecular chemical biology1 is to generate ligands capable of solvent exposed protein‐surface recognition for the purpose of orthosteric protein–protein interaction (PPI) inhibition 2, 3, 4. Inhibition of PPIs is considered challenging in view of the fact that such interactions involve extended and less well‐defined surfaces than the “lock‐and‐key”‐like interfaces that have historically proven to be tractable targets for drug‐discovery 4.…”

“…Inhibition of PPIs is considered challenging in view of the fact that such interactions involve extended and less well‐defined surfaces than the “lock‐and‐key”‐like interfaces that have historically proven to be tractable targets for drug‐discovery 4. Several supramolecular scaffolds have been explored as templates upon which to elaborate ligands for selective and high affinity protein‐surface binding,5 including: porphyrins,6, 7, 8, 9 calixarenes,9, 10, 11, 12, 13 cucurbiturils,14, 15 molecular clips,16, 17 ruthenium(II) tris‐chelates18, 19, 20, 21, 22, 23 and other ligands 24, 25, 26, 27.…”

Peptide‐Directed Binding for the Discovery of Modulators of α‐Helix‐Mediated Protein–Protein Interactions: Proof‐of‐Concept Studies with the Apoptosis Regulator Mcl‐1

“…However, targeting PPIs can be difficult owing to their large hydrophobic binding surfaces 3. There are currently three commonly employed approaches to develop modulators of PPIs:4 fragment screening,5 computational screening and drug design,6 and the exploration of peptides and peptidomimetics 7.…”

“…There are currently three commonly employed approaches to develop modulators of PPIs:4 fragment screening,5 computational screening and drug design,6 and the exploration of peptides and peptidomimetics 7. However, computational design and fragment screening require large libraries of molecules and extensive synthetic work, often resulting in non‐selective compounds 3. Peptides are challenging drug leads because in vivo their efficacy can be compromised owing to a loss of secondary structure, poor cellular uptake, and susceptibility to proteolysis 8…”