XLA-P2 is a very recently discovered novel antimicrobial peptide (AMP) that also demonstrates hemolytic activity which makes it a promising candidate in anticancer drug discovery.  

This study was primarily focused on using computational techniques to investigate the aptness of XLA-P2 as an anticancer agent. The optimized XLA-P2 structure was obtained from quantum mechanical calculations with AM1 level of theory and that structure was used in reverse docking calculations to identify the potential biological targets. From many potential targets, the human Akt-1 protein was selected due to its high fit score value and its vast involvement in enhancing the proliferation of the cancer cells wherein it is overexpressed.

Molecular docking calculations were used to study the binding of XLA-P2 to the Pleckstrin Homology (PH) of the selected target since PH domain targeting has been shown to be more effective.  Prior to docking calculations, XLA-P2 and the protein were equilibrated in the condensed phase 50 ns and 100 ns MD simulations respectively. The stability of ligand-target complex was confirmed with a 200ns classical molecular dynamics simulation.

The binding analysis shows that XLA-P2 binds to the PH domain with -4.58 kcal/mol and with four hydrogen bonds which are Lys¹⁴, Lys²⁰, Arg⁸⁶ and Thr⁸⁷. Further, residues, Lys¹⁴ and Arg⁸⁶ were identified as essential ligand binding residues whereas Lys²⁰ recognized as stabilizing residue.

This study has clearly shown that XLA-P2 is a highly potential candidate that can be further improved as an AKT-1 inhibiting anticancer drug. 

Keywords: AMP, Molecular docking, Akt-1, PH domain, MD simulations