Abstract
Protein–protein interactions (PPIs) execute many fundamental cellular functions and have served as prime drug targets over the last two decades. Interfering intracellular PPIs with small molecules has been extremely difficult for larger or flat binding sites, as antibodies cannot cross the cell membrane to reach such target sites. In recent years, peptides smaller size and balance of conformational rigidity and flexibility have made them promising candidates for targeting challenging binding interfaces with satisfactory binding affinity and specificity. Deciphering and characterizing peptide–protein recognition mechanisms is thus central for the invention of peptide-based strategies to interfere with endogenous protein interactions, or improvement of the binding affinity and specificity of existing approaches. Importantly, a variety of computation-aided rational designs for peptide therapeutics have been developed, which aim to deliver comprehensive docking for peptide–protein interaction interfaces. Over 60 peptides have been approved and administrated globally in clinics. Despite this, advances in various docking models are only on the merge of making their contribution to peptide drug development. In this review, we provide (i) a holistic overview of peptide drug development and the fundamental technologies utilized to date, and (ii) an updated review on key developments of computational modeling of peptide–protein interactions (PepPIs) with an aim to assist experimental biologists exploit suitable docking methods to advance peptide interfering strategies against PPIs.
Highlights
Delivering drugs to patient neoplasms is a major and ongoing clinical challenge
In addition to highly accurate predictions made by PIPER-FlexPepDock, another recently developed method HPEPDOCK used an ensemble of peptide conformations for blind global docking and obtained significantly higher success rates as well as lower simulation time required than pepATTRACT [105,109]
Peptides have attracted a lot of attention and the number of approved peptide biotherapeutics has been on the incline over the recent decades
Summary
Delivering drugs to patient neoplasms is a major and ongoing clinical challenge. In addition to peptide-based natural hormone analogs, peptides have been developed as drug candidates to disrupt protein–protein interactions (PPIs) and target or inhibit intracellular molecules such as receptor tyrosine kinases [5,6]. These strategies have turned peptide therapeutics into a leading industry with nearly 20 new peptide-based clinical trials annually. Understanding the molecular recognition mechanism and delineating binding affinity for PPIs is a complex challenge for both computational biologists and protein biochemists This is largely because small molecules are superior in binding to deep folding pockets of proteins instead of the larger, flat and hydrophobic binding interfaces that are commonly present at PPI complex interfaces [9].
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