Analysis of the Binding of Aripiprazole to Human Serum Albumin: The Importance of a Chloro-Group in the Chemical Structure.
Analysis of the Binding of Aripiprazole to Human Serum Albumin: The Importance of a Chloro-Group in the Chemical Structure.
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DOI：
10.1021/acsomega.8b02057
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发表时间：
2018-10-31
期刊：
影响因子：
4.1
通讯作者：
Otagiri M
中科院分区：
文献类型：
--
作者：
Sakurama K;Kawai A;Tuan Giam Chuang V;Kanamori Y;Osa M;Taguchi K;Seo H;Maruyama T;Imoto S;Yamasaki K;Otagiri M
阿立哌唑（阿普）是一种喹啉酮衍生物，是一种用于治疗精神分裂症的非典型抗精神病药物。阿普分布广泛，99%以上的阿普和主要活性代谢产物脱氢ARP与血浆蛋白结合。然而，关于阿普的蛋白质结合的信息是有限的。在这项研究中，我们报告了阿普的蛋白结合的系统研究。阿普和结构相关的化合物与人血清白蛋白（HSA）的相互作用进行了研究，使用平衡透析，圆二色谱（CD）光谱，荧光探针位移，和X-射线晶体学分析。发现阿普及其主要代谢产物脱氢ARP与HSA的结合亲和力（nK）显著高于其他结构相关化合物。平衡透析实验和CD光谱数据的结果表明，连接到阿普分子中的苯基哌嗪环的氯基团在这些配体与HSA的结合中起主要作用。此外，荧光探针置换结果表明，阿普似乎结合在亚结构域III的位点II口袋。详细的CD光谱分析表明，连接到苯基哌嗪环的氯基团可以控制阿普分子的几何形状时，在网站II结合口袋中的绑定。对ARP-HSA复合物的X-射线晶体学分析表明，阿普上二氯苯哌嗪3-位上的氯原子与HSA中Cys 392的硫原子之间的距离为3.4-3.6 π。在与地西泮复合的HSA结构中也观察到类似的卤键相互作用，地西泮也含有氯基。因此，负责阿普与蛋白质结合的机制应该与评估阿普在各种临床情况下的药代动力学和药效学以及设计新药有关。
Aripiprazole (ARP), a quinolinone derivative, is an atypical antipsychotic drug that is used in the treatment of schizophrenia. ARP has an extensive distribution and more than 99% of the ARP and dehydro-ARP, the main active metabolite, is bound to plasma proteins. However, information regarding the protein binding of ARP is limited. In this study, we report on a systematic study of the protein binding of ARP. The interaction of ARP and structurally related compounds with human serum albumin (HSA) was examined using equilibrium dialysis, circular dichroism (CD) spectroscopy, fluorescent probe displacement, and an X-ray crystallographic analysis. The binding affinities (nK) for ARP and its main metabolite, dehydro-ARP with HSA were found to be significantly higher than other structurally related compounds. The results of equilibrium dialysis experiments and CD spectral data indicated that the chloro-group linked to the phenylpiperazine ring in the ARP molecule plays a major role in the binding of these ligands to HSA. Furthermore, fluorescent probe displacement results indicated that ARP appears to bind at the site II pocket in subdomain III. A detailed CD spectral analysis suggests that the chloro-group linked to the phenylpiperazine ring may control the geometry of the ARP molecule when binding in the site II binding pocket. X-ray crystallographic analysis of the ARP–HSA complex revealed that the distance between the chlorine atom at the 3-positon of dichlorophenyl-piperazine on ARP and the sulfur atom of Cys392 in HSA was 3.4–3.6 Å. A similar halogen bond interaction has also been observed in the HSA structure complexed with diazepam, which also contains a chloro-group. Thus, the mechanism responsible for the binding of ARP to a protein elucidated here should be relevant for assessing the pharmacokinetics and pharmacodynamics of ARP in various clinical situations and for designing new drugs.
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DOI：
10.1016/j.jchromb.2015.09.041
发表时间：
2016-05-15
期刊：
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
影响因子：
--
作者：
Anguizola J;Debolt E;Suresh D;Hage DS
通讯作者：
Hage DS
影响因子：
5.6
作者：
Kragh-Hansen, Ulrich;Watanabe, Hiroshi;Otagiri, Masaki
通讯作者：
Otagiri, Masaki
影响因子：
7.3
作者：
Oshiro, Y;Sato, S;Nishi, T
通讯作者：
Nishi, T
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC