The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented. We hypothesized that sugammadex would attract rocuronium and vecuronium via interaction with the sugammadex side-chain “tentacles”, as previously suggested.


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 9 other drugs, whose binding affinities have been experimentally determined. These observations hinted that high concentrations of unbound sugammadex could bind to propofol, potentially altering its pharmacokinetic profile. We tested this experimentally in in vitro cortical slices.


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 ~120 ns (distance 0.35 ± 0.12 nm). Vecuronium formed fewer hydrogen bonds with sugammadex than did rocuronium, hence was less avidly bound. For the other molecules, our computational results showed good agreement with the available experimental data, showing a clear bi-logarithmic relation between the relative binding free energy and the association constant (R2=0.98). Weaker binding was manifest by periodic unbinding. The brain slice results confirmed the presence of a weak propofol-sugammadex interaction.


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.