Abstract
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.
Financial & competing interests disclosure
J Audie, DJ Diller, AS Bayden and M Jarosinski are employees of and stakeholders in CMDBioscience, a company that specializes in computer-enabled peptide drug design. J Swanson owns and operates ChemModelling and works as a consultant for CMDBioscience. All authors stand to gain professionally and financially if CMDBioscience is successful. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.