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Cyclotide Structure–Activity Relationships: Qualitative and Quantitative Approaches Linking Cytotoxic and Anthelmintic Activity to the Clustering of Physicochemical Forces
Figure 8
A dendrogram showing the hierarchical clustering of 75 cyclotides based on their molecular descriptors.
The descriptors considered include the lipophilic moment (LM), exclusive lipophilicity 
, positively charged surface area (ES) and HBD amphipathic moment (EM). The left column shows the cyclotides' labels, which indicate the subgroup to which they belong (indicated by the letter ‘G’), relative activity (indicated by the letter ‘A’) and a subfamily-specific letter (M for Möbius, B for bracelet, H for hybrid and L for linear). The relative distance measures the physicochemical dissimilarity between cyclotides in respect to the normalized scale. The relative activity was calculated with respect to the cytotoxicity of kB1, and three levels of activity were defined: A0 for peptides whose relative activity ranges of >1.0, A1 for those with relative activities between 0.2 and 1.0, and A2 for those with relative activities of <0.2. Those with unknown activity were labeled An. Aside from [Mee]-cyO2 and varv A, all of the cyclotides were assigned to the same activity groups for both cytotoxicity and anthelmintic activity. The cyclotide subfamilies clustered into different subgroups, with most of the Möbius cyclotides being in groups 1 (red) and 2 (green), and all of the bracelets being in group 3 (blue). Aside from psyle A (H5), all of the hybrid cyclotides clustered in group 2. Group 2 also contains some unusual cyclotides that exhibit high or intermediate activity, namely cyO14 (M33), cyO15 (M34), cyO16 (M35), [T20K, S22K]-kB1 (M19) and [S22K]-kB1 (M22). These cyclotides are all rich in lysines.
doi: https://doi.org/10.1371/journal.pone.0091430.g008