Mapping the structure–activity landscape of non-canonical peptides with MAP4 fingerprinting

Peptide structure–activity/property relationship (P-SA/PR) studies focus on understanding how the structural variations of peptides influence their biological activities and other functional properties. This knowledge accelerates the rational design and optimisation of peptide-based drugs, biomaterials, or diagnostic agents. These studies examine peptide structures from their primary sequences, essentially encoded from the 20 amino acids. Current approaches often exclude peptide libraries with post-translational and synthetic modifications. The molecular fingerprint MAP4 was recently developed to map complex molecules' sequence/structure diversity, including peptides. This study used structure–activity landscape modelling to conduct the P-SA/PR studies of an exemplary dataset of 223 antimicrobial peptides against methicillin-resistant Staphylococcus aureus (MRSA). To this end, we employed the MAP4 fingerprint to represent the chemical structures of the peptides, study their relationship(s) with the antibacterial activity, and seek the potential activity cliff(s). We identified critical residues and structural motifs that play a crucial role in the anti-MRSA activity of the peptides. This is the first computational study to systematically explore the activity landscape of peptides with non-canonical residues, emphasising the quantification of structural similarity.