Background: Human serum albumin (HSA), the most abundant protein in plasma,
is a monomeric multi-domain macromolecule with at least nine binding sites for endogenous
and exogenous ligands. HSA displays an extraordinary ligand binding capacity as a depot and
carrier for many compounds including most acidic drugs. Consequently, HSA has the potential
to influence the pharmacokinetics and pharmacodynamics of drugs.
Objective: In this review, the structural determinants of drug binding to the multiple sites of
HSA are analyzed and discussed in detail. Moreover, insight into the allosteric and competitive
mechanisms underpinning drug recognition, delivery, and efficacy are analyzed and discussed.
Conclusion: As several factors can modulate drug binding to HSA (e.g., concurrent administration
of drugs competing for the same binding site, ligand binding to allosteric-coupled
clefts, genetic inherited diseases, and post-translational modifications), ligand binding to HSA
is relevant not only under physiological conditions, but also in the pharmacological therapy