Encapsulation Dynamics of Neuromuscular Blocking Drugs by Sugammadex

Abstract

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. We hypothesized 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 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. 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 ~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. 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.

Synthesis and Characterization of Propofol‐Like Compounds, Anticancer Activities and Investigation of Their Anesthetic Effects by Molecular Docking

“…Overall, the use of in silico technologies is a fruitful practice, not only to improve our understanding of drug‐receptor interactions at the molecular level, but also to pave the way for a brighter future in terms of cheaper and safer drugs. It has emerged that this could increase access to anesthesia for larger and diverse patient groups in developed or less developed countries and should be one of the main research goals in this area [17] …”

The arousal effect of sugammadex reversal of neuromuscular blockade differs with anesthetic depth in propofol-remifentanil anesthesia: a randomized controlled trial

“…However, unexpected and sudden arousal after sugammadex use baffles clinicians, and further investigation of the effect of sugammadex on arousal is required. Recent studies have reported that sugammadex can encapsulate other drugs, such as propofol and remifentanil, in addition to non-steroidal neuromuscular blockers 5 . Another study reported that low dose sugammadex administration (2 mg kg −1 ) provoked a lighter anesthesia depth pattern characterized by an increase in beta activity and a decrease in delta activity, without clinical signs of awakening when administering sugammadex in deep sevoflurane anesthesia 6 .…”

Anesthesia, Coming of Age in the World of Modern In Silico Drug Design

“…The implementation of modern in silico computational chemistry and molecular modeling in this issue of Anesthesiology by Irani et al . 1 demonstrates the value that can be brought to our detailed understanding of pharmaceutical mechanisms at a molecular level and how this correlates with clinical effect. The authors stated three goals for their examination of sugammadex interactions with specific drugs: to examine the molecular dynamics of the encapsulation process of rocuronium and vecuronium by sugammadex; to validate the simulation technique by comparing the simulated binding strengths between sugammadex and 11 other compounds with previously published, experimentally obtained affinity data; and to characterize the patterns of sugammadex low-affinity binding with propofol.…”

“…It is in light of this that other methods of molecular modeling were developed using more simplistic yet reasonably accurate methods of calculation. While there are many validated variations of the “forcefields” used to describe such intermolecular and intramolecular interactions that are both commercially available and open-source as implemented by Irani et al , 1 most consist of a series of parameters that have been developed to allow the bond length, bond angle, and bond torsion interactions to be accurately treated using the mathematics of the simple spring potential. These are further supplemented to consider equations involving the interactions between partial atomic charges, as well as hydrophobic interactions through various van der Waals potentials.…”

“…The density of trained anesthesia providers is extraordinarily lower in some low-income countries than in most high-income countries, with anesthesia mortality rates correspondingly as much as 1,000 times higher. 13 Overall, the use of new in silico technologies as illustrated by Irani et al 1 can be efficiently implemented not only to improve our understanding of drug-receptor interactions at a molecular level but also to possibly pave the way for a brighter future for our specialty through cheaper, safer drugs. This could allow increased access to the "miracle of anesthesia" for an even larger and more diverse group of ill patients throughout both developed and underdeveloped countries and should be one of the major research goals within our specialty.…”