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Sugammadex is a modified cyclodextrin: 8 member sugar ring with carboxyl thioether extensions. Rocuronium is an aminosteroid, 4 steroid rings and one protonated amine group.

Sugammadex binds rocuronium really tightly. The reason for this is straightforward - lipophilic interactions with the inner cavity of the cyclodextrin, which is the perfect size because of the thioether extensions. The negatively charged carboxylate groups lock into place with the protonated amine.

But the question asks how the rocuronium is initially drawn into the cavity, which makes less sense. I've only found one reference to this in the literature, in a figure caption that says the carboxylate groups interact with the four steroid rings.

But how? The rings are not aromatic, so there is no anion-pi interaction. One would think the positively charged amine would interact with the carboxylate groups far more often, leading to the wrong orientation. If anything, the hydrophobic rings should be repulsed by the negative charge?

sugammadex binding rocuronium

encapsulation

Figure 6: Encapsulation process: Sugammadex carboxyl groups interact with steroidal rings A, B, C, and D, drawing the aminosteroidal NMBA molecule into the cavity where additional non-covalent attractions hold the molecule securely in place.


Reference:NCBI

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  • $\begingroup$ Could you provide the reference that describes that interaction? $\endgroup$ – jerepierre Oct 2 '14 at 20:07
  • $\begingroup$ Sorry, I should have done that in the first place. Edited with the figure and a link. $\endgroup$ – user5434 Oct 2 '14 at 21:19
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After consulting with a professor, the answer seems obvious.

The two negative charges repel each other when the free cyclodextrin molecule is in solution, resulting in an "open" conformation that has the carboxylate groups facing "out". The thioether chains interact with the rocuronium as it is drawn into the large open face of the molecule. As the positively charged nitrogen moves into place, the carboxylate groups "close", and lock the drug into place.

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I'm not convinced that the rocuronium molecule can be "drawn" only from that side of the sugammadex molecule (which is the substituted lower rim side, not the cavity side, but never mind, that’s pretty large γ-cyclodextrin) (but also I'm not cyclodextrin supramolecular chemistry expert).

There are some multi-level computer simulations done in China recently.[1] They have done some molecular dynamics, but they don't provide their trajectory data. Anyway, that trajectory is only several Å, from some pre-docked position to the optimized docked position.

There's a nice older study,[2] not mentioned in your reference, working with sugammadex-like compound with bulkier substituents (carboxyphenylthio instead of carboxyethylthio), and besides hypothesizing on closed and open conformations because of π-π interactions of the aromatics, they show (or remind) that rocuronium can have different conformations where the morpholine residue (at right at your graphics, opposite to the quaternary ammonium) can be either in-plane, or perpendicular to the plane, so that it can nicely accommodate, or somewhat lock-in once it enters the cavity (besides other interactions), but they seem to also assume that it's the (only) entering side, which I'm not convinced of.

Encapsulation is rather statistical dynamics process with thermodynamic equilibrium, than a sucking in.

They also have a nice X-ray structure data of the encapsulation complex,[3] but again, that's not sugammadex, exactly. Its X-ray crystal structure is in the Angew. Chem. article[4], the substrate is in the same orientation, but I think it's not because it can enter from one side only with the signle orientation only, but rather because of the electrostatic stabilization.

References:

  1. Li, L.; Zhou, Y.; Wang, Z.; Wu, C.; Li, Z.; Sun, C.; Sun, T. Theoretical Studies on the Mechanism of Sugammadex for the Reversal of Aminosteroid-Induced Neuromuscular Blockade. Journal of Molecular Liquids 2018, 265, 450–456.
  2. Cooper, A.; Nutley, M.; MacLean, E. J.; Cameron, K.; Fielding, L.; Mestres, J.; Palin, R. Mutual Induced Fit in Cyclodextrin–Rocuronium Complexes. Org. Biomol. Chem. 2005, 3 (10), 1863–1871.
  3. Crystallography Open Database – Information card for entry 7150103
  4. Bom, A.; Bradley, M.; Cameron, K.; Clark, J. K.; Egmond, J. van; Feilden, H.; MacLean, E. J.; Muir, A. W.; Palin, R.; Rees, D. C.; et al. A Novel Concept of Reversing Neuromuscular Block: Chemical Encapsulation of Rocuronium Bromide by a Cyclodextrin-Based Synthetic Host. Angewandte Chemie International Edition 2002, 41 (2), 265–270
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