Peptide-Based Drug Design

Cationic Antimicrobial Peptides 147
29 physicochemical properties for groups of related peptides that were varied
at certain positions. These properties included calculated properties such as
molecular weight and empirical values such as HPLC retention times at nine
different conditions of pH and eluent mixture. The first three principal components
were named “z values” and were obtained from these 29 properties. They
represent a mixture of these 29 properties in fixed proportions, the so-called
“loadings”. These loadings represent the importance of each of the 29 properties
on the z value. These z values have the important property that they describe
variations in the data independently of one another (they are orthogonal in a
mathematical sense). The value of each of the three z values is related approximately
to hydrophilicity/hydrophobicity, volume, and electronic properties. The
result is that the properties of highly similar peptides can be represented quite
well by the three z values in place of the original 29 descriptors used by Hellberg
et al. (75) orthe20usedbyStrometal.(73). Lejon et al. (71) found that
similar results could be obtained for the same data set of 20 lactoferricin and
lactoferricin derivates using the z values to describe the effect of amino acid
substitution on peptide helicity, HPLC retention times, and antibacterial activity.
Further studies on an expanded set of peptides (72) again demonstrated good
predictive ability using z values for peptide analogues where only a few amino
acid substitutions were made. However, as noted by the authors, the predictions
became lower in accuracy when more than one or two substitutions were made
in a single peptide; this indicates the limitation of the approach for more general
antibacterial prediction.
3.2.2. QSAR of Protegrin Analogues and De Novo Peptides
In another approach, Frecer et al. (76) used a de novo design strategy to
produce synthetic peptides with structural similarity to cyclic �-sheet defense
peptides such as protegrin. The peptides were designed based on assumptions
of mechanisms of antibacterial activity and the importance of charge, amphipathicity
and lipophilicity (hydrophobicity). Peptides were designed using a
combination of molecular modeling, molecular dynamics, and docking methods
to have a structure containing tandemly repeated cationic and nonpolar amino
acids that forms an amphipathic �-hairpin that binds to lipid A (an important
surface structure on gram-negative bacteria). A total of seven peptides were
constructed and synthesized for QSAR analysis. Only three descriptors were
used to model antibacterial, hemolytic, and cytotoxicity: total charge, an amphipathicity
index, and a lipophilicity index. Antimicrobial activity was found to
give good correlation with charge and amphipathicity, while hemolytic activity
was largely determined by lipophilicity, and cytotoxic effects on monocytes
were due mainly to charge and amphipathicity index. This suggested a strategy