Crystallographic Survey of Albumin Drug Interaction and Preliminary Applications in Cancer Chemotherapy

Abstract

An overview of the results of a comprehensive crystallographic structural survey of drug binding to human albumin at atomic resolution is presented. More than 350 complexes were examined, ultimately producing more than 200 structures with representatives in every major therapeutic category. The survey indicated 12 independent drug‐binding locations dominated by the three sites located within subdomains IIA, IIIA, and IB. Site IB, the most structurally accommodating site on albumin, revealed a propensity for large heterocyclic ligands and showed the highest overall binding frequency at 49%. Details of IB ligand‐binding chemistry are presented for several ligands including the camptothecin, anthracyclin, and podophylotoxin families of oncology drugs. The results from the survey were used to establish a therapeutic drug combination approach that favorably alters the albumin‐based pharmacokinetics of several highly cytotoxic oncology drugs leading to marked improvements in safety and efficacy. Examples are presented for selected applications of improving the albumin‐based pharmacokinetics of this information in drug development to improving the safety and efficacy of highly cytotoxic drugs for several important families of oncology drugs.

Albumin nanostructures as advanced drug delivery systems

“…A binding pocket in the subdomain IB has recently been recognized as a secondary binding site for some other compounds with different properties such as indomethacin, iophenoxic acid, naproxen, myristic acid, warfarin, lidocaine, and bilirubin [29]. Because of this finding, it has been proposed that subdomain IB could be a third drug-binding region of HSA [51,52] and therefore the ‘Three-Site Model’ for drug-binding regions of HSA was proposed [29]. In a recent study, Wang et al investigated the albumin-binding interactions with anticancer cytotoxic drugs such as camptothecin, etoposide, teniposide, bicalutamide, and idarubicin at the scale of atomic details [32].…”

The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery

“…Crystallographic analysis of cancer drugs binding to albumin demonstrates that they preferably bind DIB, rather than Drug sites 1 and 2 [45], and DIB is now considered Drug site 3 [50]. Interestingly, in a recent study where more than 200 atomic structures of human albumin in complex with various pharmaceuticals and endogenous ligands were analysed, small hydrophobic and anionic drugs showed preference for Drug sites 1 and 2, while complex heterocyclic ligands preferred Drug site 3 [51]. As ligands and drugs may compete for the same binding sites on albumin, their effect will depend on the presence of competitors, which results in their free fractions relative to the albumin-bound.…”

Structural Evidence of Perfluorooctane Sulfonate Transport by Human Serum Albumin

“…13 Sudlow found two primary drug-binding sites on the protein, named Sudlow sites I and II. 14,15 The first crystallographic structure of HSA showed that HSA is a heart-shaped protein, which is composed of 585 amino acid residues with three structurally homologous domains (I, II, and III).…”