Structure of the Amodiaquine-FPIX Oxo Dimer Solution Complex at Atomic Resolution
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- 作者：Angel C. de Dios ; Leah B. Casabianca ; Andrew Kosar ; and Paul D. Roepe
- 刊名：Inorganic Chemistry
- 出版年：2004
- 出版时间：December 13, 2004
- 年：2004
- 卷：43
- 期：25
- 页码：8078 - 8084
- 全文大小：154K
- 年卷期：v.43,no.25(December 13, 2004)
- ISSN：1520-510X
文摘
Using NMR inversion recovery experiments and XPLOR distance restraint calculations, we recently deduced thestructure of ferriprotoporphyrin IX (FPIX) heme 
oxo dimer-antimalarial drug complexes for chloroquine (CQ),quinine (QN), and quinidine (QD) at atomic resolution [A. Leed et al., Biochemistry 2002, 41, 10245-55]. Usingsimilar methods, we now report an unexpected structure for the complex formed between FPIX and the relateddrug amodiaquine (AQ). The deduced structure is further supported by comparing AQ chemical-shift data to restrictedHartree-Fock calculations. The structure further highlights the critical nature of quinoline drug side-chain compositionin stabilizing noncovalent association to FPIX. Heme Fe-AQ proton distances are longer, relative to those of theCQ complex, and the AQ aromatic side chain seems to have a significant role in stabilizing the complex. Relativeto the FPIX-CQ complex, a similar 2:1 stoichiometry was determined for the AQ complex, in contrast to a 4:1stoichiometry previously suggested from calorimetry data. These solution structures add to our rapidly growingunderstanding of the mechanism of quinoline antimalarial drug action and will help elucidate the mechanism(s) ofquinoline antimalarial drug resistance phenomena.
oxo dimer-antimalarial drug complexes for chloroquine (CQ),quinine (QN), and quinidine (QD) at atomic resolution [A. Leed et al., Biochemistry 2002, 41, 10245-55]. Usingsimilar methods, we now report an unexpected structure for the complex formed between FPIX and the relateddrug amodiaquine (AQ). The deduced structure is further supported by comparing AQ chemical-shift data to restrictedHartree-Fock calculations. The structure further highlights the critical nature of quinoline drug side-chain compositionin stabilizing noncovalent association to FPIX. Heme Fe-AQ proton distances are longer, relative to those of theCQ complex, and the AQ aromatic side chain seems to have a significant role in stabilizing the complex. Relativeto the FPIX-CQ complex, a similar 2:1 stoichiometry was determined for the AQ complex, in contrast to a 4:1stoichiometry previously suggested from calorimetry data. These solution structures add to our rapidly growingunderstanding of the mechanism of quinoline antimalarial drug action and will help elucidate the mechanism(s) ofquinoline antimalarial drug resistance phenomena.