Subdomain IB Is the Third Major Drug Binding Region of Human Serum Albumin: Toward the Three-Sites Model

Abstract

According to the conventional view, noncovalent association of small molecules with human serum albumin (HSA) occurs principally at the so-called Sudlow's sites located in subdomain IIA and IIIA. By employing a circular dichroism (CD) spectroscopic approach, it is shown that biliverdin is the specific CD label of an additional drug binding area in subdomain IB. CD competition experiments disclosed the entrapment of a diverse assortment of acidic, neutral, and basic molecules within subdomain IB including anticancer agents (camptothecin, doxorubicin, daunorubicin, teniposide, suramin, tyrosine kinase inhibitors), anticoagulants (dicoumarol), various steroids (bile acids, carbenoxolone), nonsteroidal antiinflammatory drugs, natural substances (aristolochic acid, glycyrrhetinic acid), and synthetic dyes (methyl orange, azocarmine B). These finding imply that subdomain IB can be considered as the third major drug binding region of HSA featured with promiscuous ligand recognition ability. Additionally, subdomain IB is allosterically coupled with the Sudlow's sites, the ligand binding of which is shown to alter the HSA binding mode and affinity of biliverdin and hemin. Brief case studies are presented to illustrate how the evaluation of spectral changes of tetrapyrrole CD probes gains new insight into the HSA binding properties of endogenous as well as pharmaceutical compounds.

Investigation of the binding of cis/trans-[MCl4(1H-indazole)(NO)]− (M = Ru, Os) complexes to human serum albumin

“…There are seven distinct binding sites on HSA for long-chain FAs (FA1 -FA7) distributed throughout the protein in an asymmetric way [8], of which FA2, FA4, and FA5 are the highest affinity sites, as indicated by crystallographic studies [9]. The principal regions of exogenous drug binding sites are located in hydrophobic pockets in subdomains IIA and IIIA (site I and site II, respectively according to the conventional view based on Sudlow's classification) [8,10], and in the recently identified binding pocket within subdomain IB (site III) which is considered as the third major binding site [11]. Three of the seven FA binding sites overlap with the two main drug binding sites, namely FA3 and FA4 overlap with site II, and FA7 with site I [8,12].…”

Speciation of Metal Complexes of Medicinal Interest: Relationship between Solution Equilibria and Pharmaceutical Properties

“…cancer, inflammation) and aging [33][34][35][36]. The remaining 2-3% of 8 Zn(II) binds to the LMM fraction mostly to His and Cys containing binary and ternary complexes [29,32,37].…”

A Rapid and Quantitative Fluorimetric Method for Protein-Targeting Small Molecule Drug Screening

“…The binding property (e.g., binding sites, binding affinity or strength) of these molecules to serum albumins forms an important topic in pharmacokinetics. [1][2][3][4] Several analytical methods have been developed to study the binding properties of different drugs to serum albumins, such as X-ray crystallography, 5,6 nuclear magnetic resonance (NMR), [7][8][9][10][11] and surface plasmon resonance (SPR), 12,13 etc. However, these methods are constrained by either a tedious and time-consuming analyzing process (e.g., growth of single crystal for X-ray crystallographic study), requirement of specialized and expensive equipment (SPR), or in need of costly isotope labeling (NMR) for detection.…”