In Silico Discovery of LL13, a Shortened Pardaxin 6 Peptide Derivative with Anti-proliferative Activity

Liver cancer is a worldwide issue that also affects the Malaysian population. The occurrence is closely related to risk factors like chronic infections and environmental exposures. Due to the toxicity of conventional therapeutic drugs for liver cancer, bioactive peptides have emerged as a popular alternative anticancer agent. Although the full-length pardaxin from Pardachirus marmoratus was proven with anticancer effects, its concurrent haemolytic effects are yet to be resolved. Therefore, this study utilized in silico and in vitro analyses to assess cytotoxic effects induced by the shortened pardaxin derivatives. The in silico findings led to the discovery of a series of shortened pardaxin derivatives with 13 amino acids, where single residue replacement prediction by bioinformatics tools was done on the shortened sequences. Among the top five shortened derivatives, the derivative where amino acid threonine was replaced by proline, was identified as the most potential candidate, namely LL13. The LL13 peptide was predicted with improved anticancer effects, non-toxic, and alleviated haemolytic effects as compared to its parental peptide. The subsequent cytotoxicity testing further validated its selective toxicity against liver cancer cells, HepG2 cells, with relatively lower killing effects on the normal cells, Vero cells. These in vitro findings validated the in silico predictions and also indicated that this peptide has potential as an anticancer drug with selective targeting capabilities. In conclusion, this study has highlighted the potential of using a combination of in silico and in vitro approaches to discover potentially shortened peptides as a novel therapeutic option for liver cancer treatment.