Theoretical studies on the mechanism of sugammadex for the reversal of aminosteroid-induced neuromuscular blockade

Abstract The mechanism of action of sugammadex in reversing neuromuscular blockers (NMBs) was theoretically studied by extensive molecular modeling (molecular docking, molecular dynamic and molecular mechanics-quantum mechanics). The NMBs-sugammadex inclusion complex was established by an enthalpy-driven process, which stabilized by hydrophobic interaction, hydrogen bonding and electrostatic interaction between NMBs and sugammadex. Furthermore, the binding energy of NMBs-sugammadex indicated that vecuronium (∆ E  = −25.29 kJ mol −1 ) had lower binding affinity to sugammadex than rocuronium (∆ E  = −34.61 kJ mol −1 ), thus the former one would be more difficult to be reversed which was consist with the phenotype of clinical trials. Molecular electrostatic potential, natural bond orbital and frontier molecular orbitals were also utilized to give explanation for the discrepancy of interaction strength between rocuronium-sugammadex and vecuronium-sugammadex inclusion complexes. In summary, the molecular modeling study made it possible to explain the different reversal efficiency of NMBs by sugammadex, which could be used to predict the drug-receptor interactions during the design phase of novel compounds development and also provide great opportunity to design novel γ-cyclodextrin-based muscle relaxant antagonists.