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Rational, computer-enabled peptide drug design: principles, methods, applications and future directions

    David J Diller

    CMD Bioscience, 5 Science Park, New Haven, CT 06511, USA

    ,
    Jon Swanson

    ChemModeling, LLC, Suite 101, 500 Huber Park Ct, Weldon Spring, MO 63304, USA

    ,
    Alexander S Bayden

    CMD Bioscience, 5 Science Park, New Haven, CT 06511, USA

    ,
    Mark Jarosinski

    CMD Bioscience, 5 Science Park, New Haven, CT 06511, USA

    &
    Joseph Audie

    *Author for correspondence:

    E-mail Address: joseph.audie@cmdbioscience.com

    CMD Bioscience, 5 Science Park, New Haven, CT 06511, USA

    Department of Chemistry, Sacred Heart University, 5151 Park Ave, Fairfield, CT 06825, USA

    Published Online:https://doi.org/10.4155/fmc.15.142

    Peptides provide promising templates for developing drugs to occupy a middle space between small molecules and antibodies and for targeting ‘undruggable’ intracellular protein–protein interactions. Importantly, rational or in cerebro design, especially when coupled with validated in silico tools, can be used to efficiently explore chemical space and identify islands of ‘drug-like’ peptides to satisfy diverse drug discovery program objectives. Here, we consider the underlying principles of and recent advances in rational, computer-enabled peptide drug design. In particular, we consider the impact of basic physicochemical properties, potency and ADME/Tox opportunities and challenges, and recently developed computational tools for enabling rational peptide drug design. Key principles and practices are spotlighted by recent case studies. We close with a hypothetical future case study.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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