Molecular encapsulation of hydroxychloroquine by cucurbit[n]urils: A combined molecular dynamics simulation and quantum chemical study.

The inclusion complexation of hydroxychloroquine (HCQ), a biologically active pharmaceutical compound, with three cucurbit[n]urils, CB[6], CB[7], and CB[8], was investigated using a combination of molecular dynamics simulations and quantum chemical calculations. The results indicate that HCQ can be accommodated within the cavity of CB[6], preferentially inserting its aliphatic side chain into the host interior. For CB[7], two distinct binding modes were observed, in which either the aliphatic chain or the aromatic quinoline ring enters the cavity, reflecting greater conformational flexibility in the host-guest association. In contrast, the larger and more adaptable cavity of CB[8] enables deeper penetration of HCQ, leading to a single, well-defined, and highly stabilized binding configuration. Among the hosts examined, CB[8] establishes the most extensive stabilizing interactions with either neutral or di-protonated forms of HCQ, particularly through contacts at its carbonyl-lined portals. In agreement with these structural features, MM/PBSA binding free-energy calculations reveal enhanced host-guest complementarity and the strongest binding affinity for the CB[8] complex. Taken together, these results identify CB[8] as the most promising cucurbituril host for applications involving HCQ encapsulation and potential drug-delivery strategies.