Origin of the Differences in Binding Affinity of Three Drug Molecules to Cucurbit[7]uril

Abstract We used a meta‐dynamics/semi‐empirical quantum mechanics/continuum solvent model (MTD/SQM/CSM) implemented in the CREST software (P. Pracht, F. Bohle, and S. Grimme, Physical Chemistry Chemical Physics , 2020, 22 , 7169–7192) to explore the binding mechanism of cucurbit[7]uril (CB[7]) with three drug molecules with similar structures: trazodone (TZ), m ‐chlorophenyl piperazine, and trimethoprim. Our computation well reproduced the measured binding trend and suggested the preferred protonation state of each drug in the complex and the extent the conformation of the drug molecule was changed upon binding. We found the overall binding affinity to be determined by a subtle balance among various interactions, including nonbonding interactions, desolvation penalty, and conformational change. The best binder to CB[7], TZ, achieved strong binding affinity by adopting the boat conformation of the piperazine ring that allowed it to form two strong intermolecular H─bonds in the doubly protonated state without causing too unfavorable desolvation penalty upon binding.