Fatty acid modulated human serum albumin binding of the β-carboline alkaloids norharmane and harmane.

TitleFatty acid modulated human serum albumin binding of the β-carboline alkaloids norharmane and harmane.
Publication TypeJournal Article
Year of Publication2013
AuthorsDomonkos, C, Fitos, I, Visy, J, Zsila, F
JournalMol Pharm
Volume10
Issue12
Pagination4706-16
Date Published2013 Dec 2
ISSN1543-8392
KeywordsAlkaloids, Binding Sites, Carbolines, Fatty Acids, Harmine, Humans, Hydrogen-Ion Concentration, Ligands, Protein Binding, Serum Albumin
Abstract

Harmane and norharmane are representative members of the large group of natural β-carboline alkaloids featured with diverse pharmacological activities. In blood, these agents are transported by human serum albumin (HSA) which has a profound impact on the pharmacokinetic and pharmacodynamic properties of many therapeutic drugs and xenobiotics. By combination of various spectroscopic methods, the present contribution is aimed to elucidate how nonesterified fatty acids (FAs), the primary endogenous ligands of HSA, affect the binding properties of harmane and norharmane. Analysis of induced circular dichroism (CD) and fluorescence spectroscopic data indicates the inclusion of the neutral form of both molecules into the binding pocket of subdomain IIIA, which hosts two FA binding sites, too. The induced CD and UV absorption spectra of harmane and norharmane exhibit peculiar changes upon addition of FAs, suggesting the formation of ternary complexes in which the lipid ligands significantly alter the binding mode of the alkaloids via cooperative allosteric mechanism. To our knowledge, it is the first instance of the demonstration of drug-FA cobinding at site IIIA. In line with these results, molecular docking calculations showed two distinct binding positions of norharmane within subdomain IIIA. The profound increase in the affinity constants of β-carbolines estimated in the presence of FAs predicts that the unbound, pharmacologically active serum fraction of these compounds strongly depends on the actual lipid binding profile of HSA.

DOI10.1021/mp400531n
Alternate JournalMol. Pharm.
PubMed ID24171410