Abstract
We investigate the binding of native β-cyclodextrin (β-CD) and eight novel β-CD derivatives with two different guest compounds, using isothermal calorimetry and 2D NOESY NMR. In all cases, the stoichiometry is 1:1 and binding is exothermic. Overall, modifications at the 3′ position of β-CD, which is at the secondary face, weaken binding by several kJ/mol relative to native β-CD, while modifications at the 6′ position (primary face) maintain or somewhat reduce the binding affinity. The variations in binding enthalpy are larger than the variations in binding free energy, so entropy–enthalpy compensation is observed. Characterization of the bound conformations with NOESY NMR shows that the polar groups of the guests may be situated at either face, depending on the host molecule, and, in some cases, both orientations are populated. The present results were used in the SAMPL7 blinded prediction challenge whose results are detailed in the same special issue of JCAMD.
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Data availability
All data and raw data files for ITC provided in supplementary information.
Code availability
https://github.com/GilsonLabUCSD/itc_fit (commit ID e9eabb0).
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MKG acknowledges funding from National Institute of General Medical Sciences (GM061300). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the funders.
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MKG has an equity interest in and is a cofounder and scientific advisor of VeraChem LLC.
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SAMPL7_Kellett_Gilson_SMILES.xlsx
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SAMPL7_Kellett_Gilson_SAMPL_ITC_complexes.xlsx
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SAMPL7_Kellett_Gilson_ITC_raw_data.zip
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SAMPL7_Kellett_Gilson_enthalpograms_SAMPL.pdf
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SAMPL7_Kellett_Gilson_NMR-R-Rimantadine.pdf
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SAMPL7_Kellett_Gilson_NMR-trans-methyl-cyclohexanol.pdf
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Kellett, K., Slochower, D.R., Schauperl, M. et al. Experimental characterization of the association of β-cyclodextrin and eight novel cyclodextrin derivatives with two guest compounds. J Comput Aided Mol Des 35, 95–104 (2021). https://doi.org/10.1007/s10822-020-00350-w
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DOI: https://doi.org/10.1007/s10822-020-00350-w