Human serum albumin (HSA) Site II (HSA Site II)

Human serum albumin (HSA) is the most abundant protein in human blood plasma, accounting for approximately 50-60% of total plasma protein [UniProt: P02768]. Site II, also known as Sudlow's site II or the indole-benzodiazepine site, is a distinct binding pocket located within subdomain IIIA of the HSA structure [PMID: 15978345]. This site is characterized by its high affinity for small, aromatic carboxylic acids, such as non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen, as well as certain benzodiazepines like diazepam [PMID: 11350175]. The binding of drugs to Site II is a critical determinant of their pharmacokinetic profile, as it dictates the free fraction of the drug available for pharmacological action and systemic clearance [PMID: 16165682]. Competitive displacement at this site is a significant mechanism for drug-drug interactions, where the addition of a second drug can increase the free concentration of a primary drug, potentially leading to adverse effects or toxicity [PMID: 10657522]. Furthermore, Site II also binds endogenous ligands such as L-tryptophan and long-chain fatty acids, which can influence drug binding capacity under various physiological conditions [PMID: 15978345]. In clinical states such as liver cirrhosis or renal failure, the binding capacity of Site II may be significantly altered due to hypoalbuminemia or the accumulation of endogenous inhibitors [PMID: 19181271]. Understanding the molecular architecture of Site II is essential for the rational design of drugs with predictable distribution and safety profiles.

Other names

Sudlow's site IIIndole-benzodiazepine siteHSA Subdomain IIIA binding siteAlbumin site II

Reversible non-covalent binding to hydrophobic pockets, which sequesters drugs in the plasma and regulates their free fraction and systemic distribution [PMID: 15978345].