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Mapping Protein-Protein Interaction Hotspots and Unveiling a Cryptic Allosteric Pocket in PLK1 PBD via Mixed-Solvent
Sutanu Mukhopadhyay1, Suman Chakrabarty1
1Department of Chemical and Biological Sciences, S. N. Bose National Centre for Basic Sciences, Kolkata, West Bengal, India.
Abstract:
Polo-like kinase 1 (PLK1) is a central regulator of mitosis and is frequently overexpressed in diverse human cancers where its elevated levels correlate with poor prognosis. Direct inhibition of the kinase domain often leads to off-target effects due to similarity with other kinases, which has driven efforts to target the polo-box domain (PBD) that mediates protein-protein interactions (PPIs). In this study, we applied mixed-solvent molecular dynamics simulations with amino acid and tripeptide probes to systematically map PPI hotspots on PLK1-PBD. Consistent with prior experimental findings, the canonical PPI site presents challenges for small-molecule drug design. Notably, our analysis revealed a previously uncharacterized allosteric pocket with favorable druggability features. The simulations further indicated that tripeptide probes increase the propensity of pocket opening, highlighting their potential utility for identifying cryptic sites in difficult-to-drug targets. Finally, information-theoretic analysis demonstrated a dynamic coupling between the canonical PPI interface and the newly identified allosteric pocket. Together, these findings provide molecular insights that enable the rational design of next-generation PLK1-PBD inhibitors with potential applications in cancer therapy.
Insights
Researchers identified a new allosteric pocket on Polo-like kinase 1 (PLK1) Polo-box domain (PBD) using molecular dynamics. This discovery offers a promising target for developing novel cancer therapies by overcoming challenges with current PLK1 inhibitors.
Area of Science:
- Molecular Biology
- Computational Chemistry
- Drug Discovery
Background:
- Polo-like kinase 1 (PLK1) is crucial for cell division and often overexpressed in cancers.
- Targeting the PLK1 Polo-box domain (PBD) is preferred over the kinase domain to avoid off-target effects.
- Identifying druggable sites on PLK1-PBD is essential for developing effective cancer therapeutics.
Purpose of the Study:
- To systematically map protein-protein interaction (PPI) hotspots on PLK1-PBD.
- To identify novel druggable pockets on PLK1-PBD.
- To provide molecular insights for designing next-generation PLK1 inhibitors.
Main Methods:
- Mixed-solvent molecular dynamics simulations.
- Utilized amino acid and tripeptide probes to map PPI hotspots.
- Information-theoretic analysis to assess dynamic coupling.
Main Results:
- A previously uncharacterized allosteric pocket with druggability potential was discovered on PLK1-PBD.
- Tripeptide probes enhanced the opening of this allosteric pocket, suggesting utility for cryptic site identification.
- Dynamic coupling was observed between the canonical PPI interface and the novel allosteric pocket.
Conclusions:
- The identified allosteric pocket on PLK1-PBD presents a promising target for drug development.
- Molecular dynamics simulations with specific probes can reveal cryptic sites in challenging targets.
- These findings enable rational design of novel PLK1 inhibitors for cancer therapy.
