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Interactive associations of drug-drug and drug-drug-drug with IIA subdomain of human serum albumin.

Molecular pharmaceutics (2012-09-27)
Feng Yang, Jiping Yue, Li Ma, Zhiyuan Ma, Mei Li, Xiaoyang Wu, Hong Liang
ABSTRACT

Owing to advantageous biochemical and pharmacological properties of human serum albumin (HSA), HSA-based drug carrier is playing an increasing role in the clinical setting. Since the IIA subdomain of HSA is a big hydrophobic cavity, we proposed that HSA delivers multiple drugs simultaneously docking on the IIA subdomain and that drugs may influence each other's binding affinity to albumin when cobinding the HSA IIA subdomain. Therefore, we studied the interactive association of drugs with the IIA subdomain of HSA by fluorescence spectroscopy and X-ray crystallography, in order to elucidate the molecular mechanism and behavior of drugs cobinding the IIA subdomain of HSA, and develop a universal structure-based model for HSA carrier design. We solved HSA-fatty acid-cinnamic acid, HSA-fatty acid-cinnamic acid-indometacin and HSA-fatty acid-cinnamic acid-indometacin-lamivudine complex structures, respectively. HSA complex structures and fluorescence quenching of HSA revealed that different drugs can regulate binding sites, binding mode and binding affinity of each other. For example, indometacin renders cinnamic acid to make reposition, and decreases binding affinity of HSA for cinnamic acid, but increases binding affinity of itself to HSA. Lamivudine makes cinnamic acid and indometacin to bind new subsites. Cinnamic acid-indometacin enhances binding affinity of lamivudine, and cinnamic acid-lamivudine increases binding affinity of indometacin, but indometacin-lamivudine decreases binding affinity of cinnamic acid to HSA. The study provided a biochemical basis for structure-guided development of HSA delivery system.

MATERIALS
Product Number
Brand
Product Description

Supelco
trans-Cinnamic acid, analytical standard
Sigma-Aldrich
trans-Cinnamic acid, 97%
Sigma-Aldrich
trans-Cinnamic acid, ≥99%
Sigma-Aldrich
trans-Cinnamic acid, natural, ≥99%, FCC, FG
Sigma-Aldrich
trans-Cinnamic acid, ≥99%, FG