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

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.