Rational, computer-enabled peptide drug design: principles, methods, applications and future directions.
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.
CMD Bioscience, 5 Science Park, New Haven, CT 06511, USA.
David J
DJ
Diller
ChemModeling, LLC, Suite 101, 500 Huber Park Ct, Weldon Spring, MO 63304, USA.
Jon
J
Swanson
CMD Bioscience, 5 Science Park, New Haven, CT 06511, USA.
Alexander S
AS
Bayden
CMD Bioscience, 5 Science Park, New Haven, CT 06511, USA.
Mark
M
Jarosinski
CMD Bioscience, 5 Science Park, New Haven, CT 06511, USA.|Department of Chemistry, Sacred Heart University, 5151 Park Ave, Fairfield, CT 06825, USA.
Joseph
J
Audie
D019295:Computational Biology; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*
D010455:Peptides