Interactive Associations of Drug鈥揇rug and Drug鈥揇rug鈥揇rug with IIA Subdomain of Human Serum Albumin
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- 作者：Feng Yang ; Jiping Yue ; Li Ma ; Zhiyuan Ma ; Mei Li ; Xiaoyang Wu ; Hong Liang
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：November 5, 2012
- 年：2012
- 卷：9
- 期：11
- 页码：3259-3265
- 全文大小：591K
- 年卷期：v.9,no.11(November 5, 2012)
- ISSN：1543-8392
文摘
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鈥檚 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鈥揻atty acid鈥揷innamic acid, HSA鈥揻atty acid鈥揷innamic acid鈥搃ndometacin and HSA鈥揻atty acid鈥揷innamic acid鈥搃ndometacin鈥搇amivudine 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鈥搃ndometacin enhances binding affinity of lamivudine, and cinnamic acid鈥搇amivudine increases binding affinity of indometacin, but indometacin鈥搇amivudine decreases binding affinity of cinnamic acid to HSA. The study provided a biochemical basis for structure-guided development of HSA delivery system.