Herein we computationally explore the modulation of the release kinetics of an encapsulated guest molecule from the cucurbit[7]uril(CB7)cavity by ligands binding to the host portal.We uncovered a correlation between t...Herein we computationally explore the modulation of the release kinetics of an encapsulated guest molecule from the cucurbit[7]uril(CB7)cavity by ligands binding to the host portal.We uncovered a correlation between the ligand-binding affinity with CB7 and the guest residence time,allowing us to rapidly predict the release kinetics through straightforward energy minimization calculations.These high-throughput predictions in turn enable a Monte-Carlo Tree Search(MCTS)to de novo design a series of cap-shaped ligand molecules with large binding affinities and boosting guest residence times by up to 7 orders of magnitude.Notably,halogenated aromatic compounds emerge as top-ranking ligands.Detailed modeling suggests the presence of halogen-bonding between the ligands and the CB7 portal.Meanwhile,the binding of top-ranked ligands is supported by^(1)H NMR and 2D DOSY-NMR.Our findings open up possibilities in gating of molecular transport through a nanoscale cavity with potential applications in nanopore technology and controlled drug release.展开更多
基金H.L.and T.-C.L.are grateful to the studentship funded by the A*STAR-UCL Research Attachment Programme through the EPSRC Centre for Doctoral Training in Molecular Modelling and Materials Science(Grant EP/L015862/1)T.-C.L.is grateful to the Research Project Grant(Grant RPG-2016-393)funded by the Leverhulme Trust+1 种基金We acknowledge the use of the UCL Myriad High Performance Computing Facility(Myriad@UCL),and associated support services,in the completion of this workThis work is partially supported financially by the Agency for Science,Technology and Research(A^(*)STAR)under grant AMDM A1898b0043,and A^(*)STAR SERC CRF Award.
文摘Herein we computationally explore the modulation of the release kinetics of an encapsulated guest molecule from the cucurbit[7]uril(CB7)cavity by ligands binding to the host portal.We uncovered a correlation between the ligand-binding affinity with CB7 and the guest residence time,allowing us to rapidly predict the release kinetics through straightforward energy minimization calculations.These high-throughput predictions in turn enable a Monte-Carlo Tree Search(MCTS)to de novo design a series of cap-shaped ligand molecules with large binding affinities and boosting guest residence times by up to 7 orders of magnitude.Notably,halogenated aromatic compounds emerge as top-ranking ligands.Detailed modeling suggests the presence of halogen-bonding between the ligands and the CB7 portal.Meanwhile,the binding of top-ranked ligands is supported by^(1)H NMR and 2D DOSY-NMR.Our findings open up possibilities in gating of molecular transport through a nanoscale cavity with potential applications in nanopore technology and controlled drug release.
