Binding of anti-Parkinson's disease drugs to human serum albumin is allosterically modulated.
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 co-administered in the treatment of Parkinson's disease, to human serum albumin (HSA). Apomorphine binds to HSA with a simple equilibrium (K(d) = 3.1 x 10(-6) M). Conversely, benserazide binds to HSA with two independent equilibria (K(d1)< or = 10(-6) M and K(d2) = 5.0 x 10(-5) M). Values of K(d) and K(d2) increase to 1.5 x 10(-5) M and 5.0 x 10(-4) M, respectively, in the presence of heme. Accordingly, the K(d) value for heme binding to HSA increases from 5.0 x 10(-7) M to 4.8 x 10(-6) M and 9.2 x 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.
Fanali
Gabriella
G
Department of Structural and Functional Biology, Center of Neuroscience, University of Insubria, Busto Arsizio (VA), Italy.
Rampoldi
Viviana
V
di Masi
Alessandra
A
Bolli
Alessandro
A
Lopiano
Leonardo
L
Ascenzi
Paolo
P
Fasano
Mauro
M
D000494:Allosteric Regulation; D000978:Antiparkinson Agents / Q000378:metabolism*; D001058:Apomorphine / Q000378:metabolism*; D001545:Benserazide / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013816:Thermodynamics; D014859:Warfarin / Q000737:chemistry / Q000494:pharmacology
D000978:Antiparkinson Agents; D012709:Serum Albumin; D006418:Heme; D014859:Warfarin; D001545:Benserazide; D001058:Apomorphine