From binding to detox: A predictive framework for supramolecular drug capture by cucurbiturils

Area of Science:

• Supramolecular chemistry
• Computational chemistry
• Drug delivery and toxicology

Background:

• Cucurbit[8]uril (CB8) is a pumpkin-like supramolecular container effective for drug delivery and detoxification.
• Its methylated form, Me4CB8, offers improved solubility while retaining biocompatibility.
• Modeling host-guest binding for Me4CB8 with complex molecules like fentanyl is challenging due to force field limitations and complex binding modes.

Purpose of the Study:

• To thoroughly characterize cucurbituril host-guest coordinations in detoxification scenarios.
• To develop and validate an accurate computational modeling workflow for supramolecular host-guest systems.
• To provide mechanistic insights into host-guest interactions for rational drug carrier design.

Main Methods:

• Utilized enhanced sampling techniques combined with highly accurate recalibrated force fields (B97-3c for host, r2SCAN-3c for guests).
• Employed fixed-charge modeling to achieve practical accuracy in host-guest system simulations.
• Integrated force-field energetics with quantum mechanics-based energy decomposition analysis for detailed interaction insights.

Main Results:

• Predicted binding thermodynamics align well with experimental data.
• Characterized multi-modal binding behaviors and the nature of host-guest interactions at an all-atom level.
• Achieved a practical accuracy limit for fixed-charge modeling of these complex supramolecular systems.

Conclusions:

• The developed workflow offers a broadly applicable strategy for understanding supramolecular detoxification systems.
• This approach enables predictive modeling for the rational design of therapeutic carriers and antidotes.
• Provides crucial mechanistic insights beyond experimental capabilities for host-guest chemistry.