Solution structures of antimalarial drug-heme complexes
Solution structures of antimalarial drug-heme complexes
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DOI：
10.1021/bi020195i
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发表时间：
2002-08-13
期刊：
影响因子：
2.9
通讯作者：
Roepe, PD
中科院分区：
文献类型：
--
作者：
Leed, A;DuBay, K;Roepe, PD
顺磁性金属中心[如在铁原卟啉IX血红素（FPIX）中发现的Fe-III]通过空间效应对附近质子自旋的弛豫率产生影响，而弛豫率主要取决于金属-质子距离。在高场核磁共振实验中，我们通过系统地改变药物与血红素的摩尔比，测量了几种与FPIX结合的抗疟疾药物的所有质子的这些效应。这些测量使我们能够确定FPIX mu-氧二聚体与抗疟疾药物氯喹（CQ）、奎宁（QN）和奎尼丁（QD）之间形成的非共价配合物的溶液结构的精确FPIX Fe-drug - H距离。利用这些距离，我们进行了距离约束计算，以确定这些配合物的最低能量解结构。结构求解为中性、单质子（+1）和双质子（+2）形式的药物。通过对这些结构的分析，我们首次看到了与FPIX结合的QN和QD之间的立体特异性差异，以及耐药疟原虫消化液泡pH变化时QN和QD溶液结构群体的差异[Dzekunov， S. M., et al. (2000) Mol. Biochem.]。中华寄生虫病杂志，2011,37 - 39。这些数据表明，CQ脂肪链在稳定FPIX-CQ复合物方面具有先前未被认识到的关键作用，并表明延长或缩短该链可能会干扰稳定性。我们还定义了FPIX：在生理FPIX浓度下形成的复合物的药物化学计量为2:1，而不是之前在较高FPIX浓度下确定的4:1和5:1化学计量[Dorn， A.等（1998）Biochem]。医药科学，2004,18(5):727-736。这些原子分辨率抗疟药物-血红素结构应有助于阐明这些药物在疟原虫恶性疟原虫血红素代谢过程中如何抑制血红素的形成，并有助于正在进行的规避抗疟药物耐药性策略的开发。
Paramagnetic metal centers [such as Fe-III found within ferriprotoporphyrin IX heme (FPIX)] exert through space effects on the relaxation rate of nearby proton spins that depend critically on the metal-proton distance. We have measured these effects for all protons of several antimalarial drugs that bind to FPIX by systematically varying the drug:heme molar ratio in high field NMR experiments. These measurements allow us to determine precise FPIX Fe-drug H distances for the solution structures of noncovalent complexes formed between FPIX mu-oxo dimers and the antimalarial drugs chloroquine (CQ), quinine (QN), and quinidine (QD). Using these distances, we then performed distance restraint calculations to determine the lowest-energy solution structures of these complexes. Structures were solved for neutral, monoprotic (+1), and diprotic (+2) forms of the drugs. Analysis of these structures allows us to visualize for the first time the stereospecific differences between QN and QD binding to FPIX and the differences in populations of QN and QD solution structures upon changes in digestive vacuolar pH for drug resistant malarial parasites [Dzekunov, S. M., et al. (2000) Mol. Biochem. Parasitol. 110, 107-124]. The data indicate a previously unrecognized key role for the CQ aliphatic chain in stabilizing FPIX-CQ complexes, and suggest how lengthening or shortening the chain might perturb stability. We also define FPIX:drug stoichiometries of 2:1 for the complexes formed at physiological FPIX concentrations, in contrast to the 4:1 and 5:1 stoichiometries previously determined at higher FPIX concentrations [Dorn, A., et al. (1998) Biochem. Pharmacol. 55, 727-736]. These atomic resolution antimalarial drug-heme structures should help elucidate how these drugs inhibit formation of hemozoin during metabolism of heme within the malarial parasite Plasmodium falciparum and assist ongoing development of strategies for circumventing antimalarial drug resistance.