Cyclodextrins (Cds) are versatile carbohydrate hosts for developing multifunctional nanostructures of pharmaceutical interest. Factors affecting the thermodynamic signatures and stability of β- and γ-Cd complexes are detailed at the atomic level. The MD/PMF-based method is combined with the description of the nature and strength of the inter-partner affinity. Naphthalene, adamantane and lycorine derivatives are used as models of drug-leading structures. Guest size affects Cd-guest contact and the inclusion degree, inducing Cd deformation, which opposes inclusion. Complexation depends on the available Cd cavity volume, as guest fitting variations and the enthalpy penalty from Cd deformation impact on the binding constants (promoting a reduction of up to 104). The often neglected Cd deformation plays, thus, an important role in the interaction behavior of larger cavity Cd-based systems, being crucial in carbohydrate-mediated recognition phenomena. It corresponds to an increase in energy of ca. 90 kJ mol−1 in the simpler analyzed model system.
Bibliographical noteAcknowledgement: The authors acknowledge the Fundação para a Ciência e a Tecnologia (FCT), Portuguese Agency for Scientific Research, through the Projects n. 016648 POCI − 01 − 0145 − FEDER − 016648 and COMPETE POCI − 01 − 0145 − FEDER − 007440. The Coimbra Chemistry Centre is also supported by FCT through the Projects PEst − OE/QUI/UI0313/2014 and POCI − 01 − 0145 − FEDER − 007630. Tânia F.G.G. Cova also acknowledges the PhD research Grant SFRH/BD/95459/2013 assigned by FCT. BFM thanks the FCT (project CENTRO − 01 − 0145 − FEDER − 000014, 2017-2020) and the Donostia International Physics Centre for financial support. The authors also wish to thank the Laboratory for Advanced Computing (LCA) of the University of Coimbra for the provision of computer time and support.
- Host–guest complexation
- Noncovalent interactions
- Molecular dynamics