Contribution of Ionization and Lipophilicity to Drug Binding to Albumin:  A Preliminary Step toward Biodistribution Prediction

Abstract

Understanding the molecular mechanisms governing albumin binding is a major challenge in absorption-distribution-metabolism-excretion prediction. To gain insight into this complex field, an ultracentrifugation method to measure the drug fraction bound to bovine serum albumin [%B(DAB)] is presented. The second part of the study shows the dependence of the experimental binding parameter on ionization and lipophilicity descriptors (pK(a) and log D(oct)(7.4) for a series of 14 structurally diverse drugs. Finally, a docking strategy is used to rationalize the findings; the results confirm the mostly nonspecific nature of the interaction of albumin with neutral ligands.

Metabolism and Pharmacokinetics of EAPB0203 and EAPB0503, Two Imidazoquinoxaline Compounds Previously Shown to Have Antitumoral Activity on Melanoma and T-Lymphomas

“…Thus, HSA could act as a carrier of these compounds in human plasma. These values seem compatible with the ionization constants and lipophilicity of EAPB0203 and EAPB0503 (Table 1), showing that these drugs are acting like weak bases (Ermondi et al, 2004). The in vitro study also demonstrated an unusual concentration dependence of EAPB0203 and EAPB0503 binding in human plasma and HSA.…”

Targeting HSP70: The second potentially druggable heat shock protein and molecular chaperone?

“…Such lipophilic compounds tend to be rather indiscriminate in their binding to proteins and previous work has shown a correlation between increasing lipophilicity and human serum albumin binding. 31 Thus, as with the previously discussed compounds, further information is required to define the precise molecular mode of action and, particularly in this case, the selectivity of apoptozole.…”

Relaxometric Study of a Series of Monoaqua GdIII Complexes of Rigidified EGTA‐Like Chelators and Their Noncovalent Interaction with Human Serum Albumin

“…The crystal structure of HSA was taken from Brookhaven Protein Databank (PDB code 1e7h www.rcsb.org/pdb) and prepared to docking calculations by adding hydrogen atoms, completing the missing side-chain and minimizing the structures with a multistep procedure. [27,28] Gd complexes were built from the crystal structure of [Gd-(EGTA)] -obtained from the CSD (entry code FAFGEZ; www.ccdc.cam.ac.uk/). Structures were energy minimized and atomic charges were calculated on all Gd atoms at the RHF level by the Mulliken method with the program Gamess [29] with a 6-31G** basis set for ligand atoms.…”