DexDesign: A New OSPREY-Based Algorithm for Designing de novo D-peptide Inhibitors

D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. We introduce DexDesign, an OSPREY-based algorithm for computationally designing de novo D-peptide inhibitors, and use it to design inhibitors of two biomedically important PDZ domains. Novel techniques enabling exponential reductions in peptide search space are presented: Minimum Flexible Set, Inverse Alanine Scans, and K*-based Mutational Scans. Designed D-peptide inhibitors are predicted to significantly improve binding affinity (KD) over the endogenous ligand.