Computational Approaches to Developing Short Cyclic Peptide Modulators of Protein-Protein Interactions

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Title: Computational Approaches to Developing Short Cyclic Peptide Modulators of Protein-Protein Interactions
Authors: Duffy, Fergal J.
Devocelle, Marc
Shields, Denis C.
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Date: 2014
Abstract: Cyclic peptides are a promising class of bioactive molecules potentially capable of modulating 'difficult' targets, such as protein–protein interactions. Cyclic peptides have long been used as therapeutics derived from natural product derivatives, but remain an underexplored class of compounds from the perspective of rational drug design, possibly due to the known weaknesses of peptide drugs in general. While cyclic peptides are non 'druglike' by the accepted empirical rules, their unique structure may lend itself to both membrane permeability and proteolytic resistance—the main barriers to oral delivery. The constrained shape of cyclic peptides also lends itself better to virtual screening approaches, and new tools and successes in this area have been recently noted. An increasing number of strategies are available, both to generate and screen cyclic peptide libraries, and best practises and current successes are described within. This chapter will describe various computational strategies for virtual screening cyclic peptides, along with known implementations and applications. We will explore the generation and screening of diverse combinatorial virtual libraries, incorporating a range of cyclization strategies and structural modifications. More advanced approaches covered include evolutionary algorithms designed to aid in screening large structural libraries, machine learning approaches, and harnessing bioinformatics resources to bias cyclic peptide virtual libraries towards known bioactive structures.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: Humana Press
Copyright (published version): 2015 Springer Science+Business Media New York
Keywords: AlgorithmsComputational biologyComputer simulationDrug designPeptide libraryPeptidesCyclicCyclic peptideProtein–protein interactionRational drug designVirtual screening
DOI: 10.1007/978-1-4939-2285-7_11
Language: en
Status of Item: Peer reviewed
Appears in Collections:CASL Research Collection
Medicine Research Collection

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