## 3 Results and Discussion
### ADMET Evaluation  
The results of a comprehensive ADMET evaluation of the thetraphotoxins used in the molecular docking and dynamics simulations are given in Figure 12, while the numerical values of these parameters are given in Table S6 of the Supplementary Materials. Papp values correspond to the intestinal permeability of drugs by using the Caco-2 monolayer cell model derived from human colorectal carcinoma and is a measure of the ease of permeation of drugs in the intestine. Good Papp scores for drugs have values that are more negative (or greater in magnitude) than \(-5.15\) cm/s [77]. Given that all the peptides have Papp scores of around \(-6\), this shows that these peptides can easily permeate into the intestine. Figure 12: Cont. Complementary to this is the HIA, which evaluates the absorption of drugs into the intestinal mucosa [78]. Although the permeability of the thetraphotoxins is high, their absorption is relatively low. Thus, the challenge arises to engineer the peptides to improve absorptivity while retaining permeability in formulation, should they eventually become therapeutics. The two seemingly contradicting results can be further investigated by in vitro experimentation to fully gauge whether the absorption of the peptide is indeed favorable or not. BBB refers to the probability that these drugs will cross the blood-brain barrier. It can be seen in Figure 12 that the BBB values are very low, indicating that the penetration of these drugs into the blood-brain barrier is highly unlikely, which is the expected case given that the samples are peptides bearing a nonzero net charge; ideal molecules that can cross the said barrier will only have molecular masses of 400 to 600 Da and be highly hydrophobic [79]. This means that the peptides are not suitable for cancers that affect the brain, as they are unable to pass through, unless conjugated to drug delivery systems to assist their passage. Cytochrome P450 (CYP) is a family of various ubiquitous enzymes which have differing functions, with isoforms 1A2, 3A4, 2C9, 2C19, and 2D6 being heavily involved in drug metabolism. Here, the thetraphotoxins are screened for their possibility to act either as a substrate or as an inhibitor to these enzymes [80; 81]. The peptides were found to have a higher probability of being a substrate for CYP1A2 and CYP2C9, while the opposite was observed for CYP3A4. In CYP2C19, the probability of the peptides being both substrates and inhibitors is quite low. For CYP2D6, the probability of these peptides being either substrates or inhibitors are comparable, both having medium probability. As the interaction of these peptides with various CYP isoforms differ, potential effects on the pharmacokinetics of other drugs taken simultaneously by target patients must be considered [82]. The half-life provides a measure of how long the drug stays within the body. Ideally, drugs should remain in the body for >0.5 h. Drugs that stay for <3 h are categorized as low, those that stay from 3 h to 8 h are moderate, and those that stay >8 h are high [83]. All the  
Figure 12: Radar plots of the ADMET characteristics of simulated thetraphotoxins. Numerical values in Cytochrome P450 plots correspond to their probability as substrates. half- life values of the peptides are over 2 h; this means that half of the amount of peptides initially administered would have already been metabolized by the body after 2 h. This provides a baseline for drug dosing. It must then be carefully studied whether the peptide has already performed its function by the time half of it has been flushed out of the body. H-HT refers to the possibility of a drug to damage the liver. Given that all of the peptides have zero as their probability for hepatotoxicity, this tells us that they are H-HT-negative, meaning they do not pose a significant threat to the liver in terms of toxicity to hepatocytes [84]. AMES, or Ames mutagenicity, refers to the probability of a therapeutic to induce genetic mutations. These genetic mutations may come as harmless, beneficial, or both [85].