A structural and thermodynamic analysis for the interaction between SBECD and neutral or protonated remdesivir has been performed using multiple ITC measurements and computational MD simulations. The global analysis of the calorimetric measurements suggests that a relatively strong complex with an association constant of ~ 104 is formed at pH 3. The need to introduce an extra parameter in the fitting model, accounting for the proportion of active CD, indicates that a large amount of structures do not effectively encapsulate the drug. The ITC measurements at neutral pH did not produce a strong signal. This could be due to a weak interaction under these conditions, but the analysis of the corresponding isotherms was not conclusive. At both pH values, the signal corresponding to the dilution of SBECD was relatively large, comparable to the signal arising from the interaction with the drug molecule. The source of this signal deserves a further study but its large value indicates that it has to be considered in the analysis between CAPTISOL and remdesivir or other drugs. Since the analysis of ITC measurements provides global thermodynamics parameters for the whole distribution of CD structures consisting CAPTISOL, it does not provide information on which number and location of SBE substitutions favor the encapsulation of the drug. This has been further investigated by MD simulations using three different structures with 7, 6 and 5 SBE substitutions respectively. These simulations provided complete energy profiles for the encapsulation mechanism, indicating that the remdesivir molecule can spontaneously bind with the CD by the secondary side and, preferentially, with the ‘‘up” orientation. The entry of the drug by
the primary side of the CD seems to be blocked by a high energy barrier for all the structures. Additionally, the simulations clearly indicate that the binding with the drug is significantly stronger when it is protonated (corresponding to low pH values) than when it is not charged (corresponding to neutral pH values). The values obtained for the association constants from the PMF profiles indicate that the binding is weaker for the structure with the lowest number of SBE substitutions, also in agreement with the ITC conclusion that the affinity is significantly dependent on the number and location of structures consisting SBECD.
Ángel Piñeiro, James Pipkin, Vince Antle, Rebeca Garcia-Fandino,
Remdesivir interactions with sulphobutylether-β-cyclodextrins: A case study using selected substitution patterns, Journal of Molecular Liquids, 2021, 117157, https://doi.org/10.1016/j.molliq.2021.117157.