Drug-likeness of cyclic peptides beyond Rule of 5

Drug discovery by small molecules accelerated after the emergence of the Rule of 5, a guideline defined by factors governing drug-likeness, such as membrane permeability and metabolic stability.To expand the drug discovery field to tough targets such as intracellular protein-protein interactions, it is critical to utilize compounds of molecular weight larger than 500 g/mol.One possible approach is to utilize cyclic peptides.However, outside the scope of the Rule of 5, general guidelines akin to the Rule of 5 have not been elucidated.In this study, we identified several governing factors needed for cyclic peptides to acquire druglikeness-here defined as the compatibility of membrane permeability and metabolic stability-outside the scope of the Rule of 5. To find a drug-likeness area and to determine the particular structural features that grant peptides druglikeness, we evaluated the membrane permeability and metabolic stability of more than 700 cyclic peptides.The results suggest that a drug-likeness area can be defined by cyclic peptides, having about 11 residues, more than half of N-alkyl amino acids, and calculated logP (ClogP) of 12.9 or more.It is noteworthy that 11residue peptides showed better possibility to be drug-like than peptides with fewer residues.This observation could be explained by the following hypothesis.Because 11-residue peptides like Cyclosporin A are structurally