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Comprehensive computational design of ordered peptide macrocycles.

Hosseinzadeh P, Bhardwaj G, Mulligan VK, Shortridge MD, Craven TW, Pardo-Avila F, Rettie SA, Kim DE, Silva DA, Ibrahim YM, Webb IK, Cort JR, Adkins JN, Varani G, Baker D
Science 358 1461-1466 (2017)
Related entries: 6be7, 6be9, 6ben, 6beo, 6ber, 6bes, 6bet, 6beu, 6bew, 6bf3, 6bf5

Cited: 72 times
EuropePMC logo PMID: 29242347

Abstract

Mixed-chirality peptide macrocycles such as cyclosporine are among the most potent therapeutics identified to date, but there is currently no way to systematically search the structural space spanned by such compounds. Natural proteins do not provide a useful guide: Peptide macrocycles lack regular secondary structures and hydrophobic cores, and can contain local structures not accessible with l-amino acids. Here, we enumerate the stable structures that can be adopted by macrocyclic peptides composed of l- and d-amino acids by near-exhaustive backbone sampling followed by sequence design and energy landscape calculations. We identify more than 200 designs predicted to fold into single stable structures, many times more than the number of currently available unbound peptide macrocycle structures. Nuclear magnetic resonance structures of 9 of 12 designed 7- to 10-residue macrocycles, and three 11- to 14-residue bicyclic designs, are close to the computational models. Our results provide a nearly complete coverage of the rich space of structures possible for short peptide macrocycles and vastly increase the available starting scaffolds for both rational drug design and library selection methods.

Articles - 6beq mentioned but not cited (1)

  1. Comprehensive computational design of ordered peptide macrocycles. Hosseinzadeh P, Bhardwaj G, Mulligan VK, Shortridge MD, Craven TW, Pardo-Avila F, Rettie SA, Kim DE, Silva DA, Ibrahim YM, Webb IK, Cort JR, Adkins JN, Varani G, Baker D. Science 358 1461-1466 (2017)


Reviews citing this publication (14)

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Articles citing this publication (57)

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