Binding of anti-Parkinson's disease drugs to human serum albumin is allosterically modulated

Gabriella Fanali, Viviana Rampoldi, Alessandra Di Masi, Alessandro Bolli, Leonardo Lopiano, Paolo Ascenzi, Mauro Fasano

Research output: Contribution to journalArticlepeer-review

Abstract

Binding of drugs to plasma proteins is an important determinant for their efficacy because it modulates drug availability to the intended target. Co-administered drugs may bind to the same protein site or to different functionally linked clefts following competitive and allosteric mechanisms. Here, we report a thermodynamic and computational characterization of the binding mode of apomorphine and benserazide, two therapeutic agents coadministered in the treatment of Parkinson's disease, to human serum albumin (HSA). Apomorphine binds to HSA with a simple equilibrium (Kd = 5 3.1 3 1 × 10-6 M). Conversely, benserazide binds to HSA with two independent equilibria (Kd1≤ 10-6 M and Kd2 5 = 5.0 × 3 10-5 M). Values of Kd and Kd2 increase to 1.5 × 3 10-5 M and 5.0 × 10-4 M, respectively, in the presence of heme. Accordingly, the Kd value for heme binding to HSA increases from 5.0 × 10-7 M to 4.8 × 10-6 M and 9.2 × 10-7 M, in the presence of saturating amounts of apomorphine and benserazide, respectively. The K d1 value for benserazide binding to HSA is not affected by heme binding, whereas apomorphine and benserazide inhibit warfarin binding to HSA, and vice versa. Therefore, apomorphine and the second benserazide molecule bind to the warfarin site, allosterically linked to the heme site. Simulated docking of apomorphine and benserazide into the warfarin site provides favorable values of intermolecular energy (-23.0 kJ mol-1 and-15.2 kJ mol -1, respectively). Considering the apomorphine, benserazide, and HSA-heme plasma levels and the possible co-administration of warfarin, these results appear relevant in the management of patients affected by Parkinson's disease.

Original languageEnglish
Pages (from-to)371-376
Number of pages6
JournalIUBMB Life
Volume62
Issue number5
DOIs
Publication statusPublished - May 2010

Keywords

  • Anti-Parkinson drugs
  • Heterotropic interactions
  • Human serum albumin
  • Molecular docking simulations
  • Thermodynamics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Clinical Biochemistry
  • Molecular Biology
  • Genetics

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