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

The pumpkin-like supramolecular container Cucurbit[8]uril (CB8) is a promising drug carrier and detoxifier that stably coordinates a series of structurally diverse guests with high association constants. Its methylated form, Me4CB8, achieves better solubility yet maintains its biocompatibility, thus serving as a promising supramolecular container. Host-guest binding involving the methylated ring is difficult to model due to the lack of an accurate transferable force field and the complex binding-mode space when coordinating structurally complex abused drugs (e.g., fentanyl with multiple aromatic rings). In this work, we present a thorough characterization of cucurbituril host-guest coordinations in a batch of practical detoxification situations with enhanced sampling techniques in conjunction with the most accurate fixed-charge parameter set. An enhanced sampling technique is coupled with high-accuracy recalibrated force fields (B97-3c calculations for host and r2SCAN-3c for abused drugs, achieving a practical accuracy limit of fixed-charge modeling of host-guest systems). While the predicted binding thermodynamics agree with experimental values, additional all-atom insights into the multi-modal binding behavior and the nature of host-guest interactions that are absent in experimental measurements are characterized using a combination of force-field energetics and quantum mechanics-based energy decomposition analysis. Overall, this workflow provides a broadly applicable strategy for the mechanistic understanding of supramolecular detoxification systems and, more importantly, predictive modeling that enables the rational design of therapeutic carriers and antidotes.