Issue 38, 2021

Rigorous analysis of the interaction between proteins and low water-solubility drugs by qNMR-aided NMR titration experiments

Abstract

Drugs are designed and validated based on physicochemical data on their interactions with target proteins. For low water-solubility drugs, however, quantitative analysis is practically impossible without accurate estimation of precipitation. Here we combined quantitative NMR with NMR titration experiments to rigorously quantify the interaction of the low water-solubility drug pimecrolimus with its target protein FKBP12. Notably, the dissociation constants estimated with and without consideration of precipitation differed by more than tenfold. Moreover, the method enabled us to quantitate the FKBP12–pimecrolimus interaction even under a crowded condition established using the protein crowder BSA. Notably, the FKBP12–pimecrolimus interaction was slightly hampered under the crowded environment, which is explained by transient association of BSA with the drug molecules. Collectively, the described method will contribute to both quantifying the binding properties of low water-solubility drugs and to elucidating the drug behavior in complex crowded solutions including living cells.

Graphical abstract: Rigorous analysis of the interaction between proteins and low water-solubility drugs by qNMR-aided NMR titration experiments

Supplementary files

Article information

Article type
Communication
Submitted
13 juil. 2021
Accepted
16 sept. 2021
First published
17 sept. 2021

Phys. Chem. Chem. Phys., 2021,23, 21484-21488

Rigorous analysis of the interaction between proteins and low water-solubility drugs by qNMR-aided NMR titration experiments

T. Hirakawa, E. Walinda, D. Morimoto and K. Sugase, Phys. Chem. Chem. Phys., 2021, 23, 21484 DOI: 10.1039/D1CP03175A

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