Potent Inhibitors of Human Organic Anion Transporters 1 and 3 from Clinical Drug Libraries: Discovery and Molecular Characterization
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- 作者：Peng Duan ; Shanshan Li ; Ni Ai ; Longqin Hu ; William J. Welsh ; Guofeng You
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：November 5, 2012
- 年：2012
- 卷：9
- 期：11
- 页码：3340-3346
- 全文大小：389K
- 年卷期：v.9,no.11(November 5, 2012)
- ISSN：1543-8392
文摘
Transporter-mediated drug鈥揹rug interactions in the kidney dramatically influence the pharmacokinetics and other clinical effects of drugs. Human organic anion transporters 1 (hOAT1) and 3 (hOAT3) are the major transporters in the basolateral membrane of kidney proximal tubules, mediating the rate-limiting step in the elimination of a broad spectrum of drugs. In the present study, we screened two clinical drug libraries against hOAT1 and hOAT3. Of the 727 compounds screened, 92 compounds inhibited hOAT1 and 262 compounds inhibited hOAT3. When prioritized based on the peak unbound plasma concentrations of these compounds, three inhibitors for hOAT1 and seven inhibitors for hOAT3 were subsequently identified with high inhibitory potency (>95%). Computational analyses revealed that inhibitors and noninhibitors can be differentiated from each other on the basis of several physicochemical features, including number of hydrogen-bond donors, number of rotatable bonds, and topological polar surface area (TPSA) for hOAT1; and molecular weight, number of hydrogen-bond donors and acceptors, TPSA, partition coefficient (log P7.4), and polarizability for hOAT3. Pharmacophore modeling identified two common structural features associated with inhibitors for hOAT1 and hOAT3, viz., an anionic hydrogen-bond acceptor atom, and an aromatic center separated by 5.7 脜. Such model provides mechanistic insights for predicting new OAT inhibitors.