Structural studies of several clinically important oncology drugs in complex with human serum albumin

Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment

“…Drug binding is via one of three sites with the first located in the IB subdomain, the second the IIA subdomain [i.e., Sudlow's site I] and the third in the IIIA subdomain [i.e., Sudlow's site II] [33]. The antiandrogen, bicalutamide, is a typical IB ligand [34] while phenylbutazone is a typical Sudlow's site I ligand which usually contains bulky heterocyclic molecules with a negative charge located in the middle of the molecule) while ibuprofen is a typical Sudlow's site II ligand which often contains an aromatic carboxylic acid with a negatively charged acidic group at one end of the molecule away from a hydrophobic center [33]. To determine whether tasquinimod binds to any of these sites in albumin, bicalcutamide, phenybutazone, and ibuprofen were tested for their dose-response ability to compete with 14 C-labeled tasquinimod binding to mouse albumin.…”

“…EPR effect was determined using Evans Blue as described previously [34] with the modification that 24 hours after the albumin in the blood of tumor bearing nude mice was labeled via IV injection of Evans Blue (EB) at a dose of 10mg/kg, the animals were anesthetized, blood collected, and then animals were perfused with saline to remove blood from the host tissues before harvesting liver, kidney, and prostate cancer xenograft tissue. The results are expressed as the concentration of EB-labeled albumin retained in the blood or specified tissue.…”

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

“…Examples of drugs that bind albumin are listed in Table 1. 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].…”

Interaction of the anticancer gallium(III) complexes of 8-hydroxyquinoline and maltol with human serum proteins

“…The B3LYP model is a combination of the Becke three-parameter hybrid functional [43] and the Lee-Yang-Parr correlation functional (which also includes density gradient terms) [44]. Three HSA X-ray crystal structures were retrieved from the RCSB Protein Data Bank (PDB) [45]-i.e., HSA complexed with warfarin (PDB code 2BXD [46]), diazepam (PDB code 2BXD [46]), and 9-aminocamptothecin (PDB code 4L8U [47]). The three proteins were superimposed by means of Chimera [48], and then the region of interest used by AutoDock was defined in order to contain all the residues of the proteins.…”