Antimicrobial cell penetrating peptides with bacterial cell specificity: pharmacophore modelling, quantitative structure activity relationship and molecular dynamics simulation

Current research has shown cell-penetrating peptides and antimicrobial peptides (AMPs) as probable vectors for use in drug delivery and as novel antibiotics. It has been reported that the higher the therapeutic index (TI) the higher would be the bacterial cell penetrating ability. To the best of our knowledge, no in-silico study has been performed to determine bacterial cell specificity of the antimicrobial cell penetrating peptides (aCPP's) based on their TI. The aim of this study was to develop a quantitative structure activity relationship (QSAR) model, which can estimate antimicrobial potential and cell-penetrating ability of aCPPs against S. aureus, to confirm the relationship between the TI and aCPPs and to identify specific descriptors responsible for aCPPs penetrating ability. Molecular dynamics (MD) simulation was also performed to confirm the membrane insertion of the most active aCPPs obtained from the QSAR study. The most appropriate pharmacophore was identified to predict the aCPP's activity. The statistical results confirmed the validity of the model. The QSAR model was successful in identifying the optimal aCPP with high activity prediction and provided insights into the structural requirements to correlate their TI to cell penetrating ability. MD simulation of the best aCPP with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer confirmed its interaction with the membrane and the C-terminal residues of the aCPP played a key role in membrane penetration. The strategy of combining QSAR and molecular dynamics, allowed for optimal estimation of ligand-target interaction and confirmed the importance of Trp and Lys in interacting with the POPC bilayer.