Encapsulation Dynamics of Neuromuscular Blocking Drugs by Sugammadex.

Background: The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented. The hypothesis was that sugammadex would attract rocuronium and vecuronium via interaction with the sugammadex side-chain "tentacles," as previously suggested. Methods: Computational molecular dynamics simulations were done to investigate docking of sugammadex with rocuronium and vecuronium. To validate these methods, strength of binding was assessed between sugammadex and a heterogeneous group of nine other drugs, the binding affinities of which have been experimentally determined. These observations hinted that high concentrations of unbound sugammadex could bind to propofol, potentially altering its pharmacokinetic profile. This was tested experimentally in in vitro cortical slices. Results: Sugammadex encapsulation of rocuronium involved a sequential progression down a series of metastable states. After initially binding beside the sugammadex molecule (mean SD center-of-mass distance = 1.17 +/- 0.13 nm), rocuronium then moved to the opposite side to that hypothesized, where it optimally aligned with the 16 hydroxyl groups (distance, 0.82 +/- 0.04 nm) before entering the sugammadex cavity to achieve energetically stable encapsulation by approximately 120 ns (distance, 0.35 +/- 0.12 nm). Vecuronium formed fewer hydrogen bonds with sugammadex than did rocuronium; hence, it was less avidly bound. For the other molecules, the computational results showed good agreement with the available experimental data, showing a clear bilogarithmic relation between the relative binding free energy and the association constant (R-2 = 0.98). Weaker binding was manifest by periodic unbinding. The brain slice results confirmed the presence of a weak propofol-sugammadex interaction. Conclusions: Computational simulations demonstrate the dynamics of neuromuscular blocking drug encapsulation by sugammadex occurring from the opposite direction to that hypothesized and also how high concentrations of unbound sugammadex can potentially weakly bind to other drugs given during general anesthesia.