Abstract
Protein-protein interactions (PPIs) mediate a large number of important regulatory pathways. Their modulation represents an important strategy for discovering novel therapeutic agents. However, the features of PPI binding surfaces make the use of structure-based drug discovery methods very challenging. Among the diverse approaches used in the literature to tackle the problem, linear peptides have demonstrated to be a suitable methodology to discover PPI disruptors. Unfortunately, the poor pharmacokinetic properties of linear peptides prevent their direct use as drugs. However, they can be used as models to design enzyme resistant analogs including, cyclic peptides, peptide surrogates or peptidomimetics. Small molecules have a narrower set of targets they can bind to, but the screening technology based on virtual docking is robust and well tested, adding to the computational tools used to disrupt PPI. We review computational approaches used to understand and modulate PPI and highlight applications in a few case studies involved in physiological processes such as cell growth, apoptosis and intercellular communication.
Highlights
Most proteins mediate complicated metabolic and signaling pathways through interaction with other proteins, either in the form of dimers or as components of larger complexes (Hunter, 2000; Stelzl et al, 2005)
These motifs are often embedded within locally unstructured protein regions but can bind their partners as short, isolated peptides acting as Protein-protein interactions (PPIs) inhibitors
We describe the use of computational methods in conjunction of other biophysical and medicinal chemistry techniques to help to understand the features of peptide ligands, necessary to design PPI disruptors peptidomimetics and peptide surrogates and describe a few examples in drug discovery and tissue engineering
Summary
Most proteins mediate complicated metabolic and signaling pathways through interaction with other proteins, either in the form of dimers or as components of larger complexes (Hunter, 2000; Stelzl et al, 2005). Protein domains involved in PPIs often bind multiple peptides that share linear motifs—common sequence patterns—like for example, the canonical SH3 domainbinding PxxP motif (Mayer, 2001). These motifs are often embedded within locally unstructured protein regions but can bind their partners as short, isolated peptides acting as PPIs inhibitors. A detailed understanding of the human interactome--the complex network of PPIs—(Luck et al, 2020) offers novel opportunities for therapeutical intervention (Milroy et al, 2014)
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