Title : Design and computational analysis of a peptide analogue with a WXXW motif: A membrane-active and reversible drug binding peptide to overcome cancer drug resistance
Abstract:
Membrane-active peptides are known for their ability to transport therapeutic agents across cellular membranes, thereby enhancing intracellular delivery. In this study, we designed a membrane-active peptide analogue by incorporating a drug-binding sequence. This modification aims to improve the binding affinity for doxorubicin while retaining membrane activity. Doxorubicin, a widely used chemotherapeutic agent, often encounters limitations such as multidrug resistance and off-target toxicity. Enhancing the interaction between the peptide analogue and doxorubicin may result in a more effective delivery platform that leverages both membrane activity and drug-binding capability. To investigate the binding dynamics of the drug-peptide complex, blind molecular docking and molecular dynamics simulations were performed in aqueous solution at room temperature. Docking identified tryptophan residues W12 and W15 within a WXXW motif as key contributors to the initial binding pose. Molecular dynamics simulations further demonstrated a transition from surface-level interaction to a more embedded binding state, with the peptide wrapping around doxorubicin. Energy decomposition analysis highlighted the dominant contribution of the WXXW motif, along with W19, in mediating the interaction. These results support the rational design of membrane-active peptide analogue as a flexible and effective drug-binding peptide, emphasising its potential in targeted drug delivery strategies. Future studies may explore the integration of the WXXW motif into peptides tailored for specific molecular targets, offering innovative avenues in drug delivery and design.
- How to rationally design membrane-active peptides for targeted drug delivery using structural modifications (e.g., WXXW motif).
- The role of computational tools like blind docking and molecular dynamics simulation in predicting and validating peptide-drug interactions.
- Mechanistic insight into drug intercalation involving key tryptophan residues (W12, W15, W19).
- Strategies to overcome cancer drug resistance through enhanced intracellular retention of chemotherapeutics.
- Application of residue energy decomposition analysis to identify drug-binding residues within peptides.
- This knowledge enables researchers to design more effective peptide-based carriers for drug delivery, especially in resistant cancer models. It is directly applicable for faculty in computational biology, medicinal chemistry and pharmacy teaching or research. The methodology also improves accuracy and efficiency in drug delivery system design by reducing experimental trial and error through pre validation of interactions computationally
