Drug-binding energetics of human alpha-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations

Huang, Johnny X., Cooper, Matthew A., Baker, Mark A., Azad, Mohammad A. K., Nation, Roger L., Li, Jian and Velkov, Tony (2012) Drug-binding energetics of human alpha-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations. Journal of Molecular Recognition, 25 12: 642-656. doi:10.1002/jmr.2221


Author Huang, Johnny X.
Cooper, Matthew A.
Baker, Mark A.
Azad, Mohammad A. K.
Nation, Roger L.
Li, Jian
Velkov, Tony
Title Drug-binding energetics of human alpha-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations
Formatted title
Drug-binding energetics of human α-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations
Journal name Journal of Molecular Recognition   Check publisher's open access policy
ISSN 0952-3499
1099-1352
Publication date 2012-12
Sub-type Article (original research)
DOI 10.1002/jmr.2221
Volume 25
Issue 12
Start page 642
End page 656
Total pages 15
Place of publication Bognor Regis, West Sussex, United Kingdom
Publisher John Wiley & Sons
Collection year 2013
Language eng
Formatted abstract
This study utilizes sensitive, modern isothermal titration calorimetric methods to characterize the microscopic thermodynamic parameters that drive the binding of basic drugs to α-1-acid glycoprotein (AGP) and thereby rationalize the thermodynamic data in relation to docking models and crystallographic structures of the drug–AGP complexes. The binding of basic compounds from the tricyclic antidepressant series, together with miaserine, chlorpromazine, disopyramide and cimetidine, all displayed an exothermically driven binding interaction with AGP. The impact of protonation/deprotonation events, ionic strength, temperature and the individual selectivity of the A and F1*S AGP variants on drug-binding thermodynamics was characterized. A correlation plot of the thermodynamic parameters for all of the test compounds revealed that an enthalpy–entropy compensation is in effect. The exothermic binding energetics of the test compounds were driven by a combination of favorable (negative) enthalpic (∆Hº) and favorable (positive) entropic (∆Sº) contributions to the Gibbs free energy (∆Gº). Collectively, the data imply that the free energies that drive drug binding to AGP and its relationship to drug serum residency evolve from the complex interplay of enthalpic and entropic forces from interactions with explicit combinations of hydrophobic and polar side-chain sub-domains within the multi-lobed AGP ligand binding cavity.
Keyword Human alpha-1-acid glycoprotein
Thermodynamics
Drug binding
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
Institute for Molecular Bioscience - Publications
 
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