Binding of Phenothiazine Drugs to Heptakis-Methylated β- Cyclodextrin Derivatives: Thermodynamics and Structure

Experimental binding data from simple, well-defined model cases such as host-guest systems, are of value in testing and training computational models of noncovalent binding, such as those used in drug discovery. Cyclodextrins (CDs), macrocycles of glucose units, form a particularly accessible class of host molecules that are water-soluble and amenable to derivatization. CDs are used for pharmaceutical formulations and can even be drugs in their own right. We used calorimetry and NMR spectroscopy to characterize the noncovalent association of native βCD and three methylated derivatives of βCD with five phenothiazine drugs. The strongest association observed, that of thioridazine and one of the methyl derivatives, exceeds the affinity of rimantidine with βCD, while methylation at the 3 position of βCD abolished binding for all of the drugs studied. The variations in binding entropy and enthalpy across the dataset demonstrate a clear pattern of entropy-enthalpy compensation. The NMR data show that all of the drugs position at least one aromatic proton at the secondary face of the CD, and most also show evidence of deep penetration of the binding site. The results of this study were used in the SAMPL9 blinded binding affinity- prediction challenge.