The Effects of Drug Complexation on the Stability and Conformation of Human Serum Albumin: Protein Unfolding

Abstract

We report different analytical methods used to study the effects of 3\'-azido-3\'-deoxythymidine, aspirin, taxol, cisplatin, atrazine, 2,4-dichlorophenoxyacetic, biogenic polyamines, chlorophyll, chlorophyllin, poly(ethylene glycol), vanadyl cation, vanadate anion, cobalt-hexamine cation, and As2O3, on the stability and secondary structure of human serum albumin (HSA) in aqueous solution, using capillary electrophoresis, Fourier transform infrared, ultraviolet visible, and circular dichroism (CD) spectroscopic methods. The concentrations of HSA used were 4% to 2% or 0.6 to 0.3 mM, while different ligand concentrations were 1 microM to 1 mM. Structural data showed drugs are mostly located along the polypeptide chains with both specific and nonspecific interactions. The stability of drug-protein complexes were in the order K(VO(2+)) 1.2 x 10(8) M(-1) > K(AZT) 1.9 x 10(6) M(-)1 > K(PEG) 4.1 x 10(5) M(-1) > K(atrazine) 3.5 x 10(4) M(-1) > K(chlorophyll) 2.9 x 10(4) M(-1) > K2,4-D 2.5 x 10(4) M-1 > K(spermine) 1.7 x 10(4) M(-1) > K(taxol) 1.43 x 10(4) M(-1) > K(Co(3+)) > 1.1 x 10(4) M(-1) > K(aspirin) 1.04 x 10(4)i(-1) > K(chlorophyllin) 7.0 x 10(3) M(-1) > K(VO(3)(-)) 6.0 x 103 M(-1) > K(spermidine) 5.4 x 10(3) M(-1) > K(putrescine) 3.9 x 10(3) M(-1)> K(As(2)O(3)) 2.2 x 10(3) M(-1)> K(cisplatin) 1.2 x 10(2) M(-1). The protein conformation was altered (infrared and CD results) with major reduction of alpha-helix from 60 to 55% (free HSA) to 49 to 40% and increase of beta-structure from 22 to 15% (free HSA) to 33 to 23% in the drug-protein complexes. The alterations of protein secondary structure are attributed to a partial unfolding of HSA on drug complexation.

Current Issues in Measurement and Reporting of Urinary Albumin Excretion

“…Albumin is a carrier for numerous small organic molecules and ions (57,(63)(64)(65)(66)(67)(68). Binding of these molecules could affect conformation of albumin (57,66,69 ).…”

“…Binding of these molecules could affect conformation of albumin (57,66,69 ). A number of other endogenous compounds, such as copper and thyroxine, bind to albumin but occupy Ͻ1% of albumin molecules in plasma.…”

Capillary electrophoresis of proteins 2005–2007

“…Recently CE has been used to measure binding of anticancer gallium(III) complexes to transferrin and serum albumin [154], novel antitumor ruthenium(III) complexes to human serum proteins [155][156][157], anticancer drugs to serum proteins [158], basic drugs to serum proteins, BSA, and a 1 -acid glyco-protein [159], theophylline to human serum albumin [160], oxindole alkaloid from Uncaria tomentosa to amyloid protein for potential treatment of Alzheimer's disease [161], new propranolol analogues to serum proteins [162], a dimeric inhibitor to 3C-like proteinase [163], roscovitine to plasma proteins [164], and drug suramin to b 2 -microglobulin [165,166]. The effect of drug complexation on stability and conformation of human serum albumin has been also studied [167].…”

Drug likeness prediction of 5-hydroxy-substituted coumarins with high affinity to 5-HT1A and 5-HT2A receptors

“…Thus, it is important to determine the fraction of unbound drugs at various stages of drug development, and during ADMET (absorption, distribution, metabolism, elimination and toxicity) parameters studies (Hogson, 2001). There is also a strong correspondence between interactions of drug candidate with plasma proteins and its pathways inside the human body, therefore computational evaluation of protein-drug energies can help in A C C E P T E D M A N U S C R I P T 3 the characterization of problems generated by protein binding (Ahmed-Ouameur et al, 2006;Curry, 2009;Flarakos et al, 2005).…”