title: QSAR analysis of antimicrobial and haemolytic effects of cyclic cationic antimicrobial peptides derived from protegrin-1.
abstract: In this paper we quantitatively analyse antimicrobial and haemolytic activities of porcine protegrin-1 (PG-1) mimetics-cyclic cationic peptides with beta-hairpin fold synthesised by Robinson et al. [Bioorg. Med. Chem.2005, 13, 2055]. The presented QSAR models, which use molecular properties related to possible mechanisms of cell membrane disruption that can be easily calculated from available data on amino acids, rationalize the relationships between sequences and antimicrobial and haemolytic potencies of the cyclic peptides. The best models obtained by application of genetic function approximation algorithm correlate antimicrobial potencies to the peptide's charge and amphipathicity index, while the haemolytic effect correlates well with the lipophilicity of residues forming the nonpolar face of the beta-hairpin. The models permit selection of site-directed residue substitutions leading to simultaneous optimization of antimicrobial and haemolytic potencies. Examples of such residue substitutions in the nonpolar face of a symmetric cyclic beta-hairpin PG-1 analogue with an ideal amphipathic structure are given.
authors.affiliation: Cancer Research Institute, Slovak Academy of Sciences, Bratislava SK-83391, Slovakia. exonfrec@savba.sk
authors.forename: Vladimir
authors.initials: V
authors.lastname: Frecer
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D011506:Proteins; C094880:protegrin-1