当前位置: X-MOL 学术J. Comput. Aid. Mol. Des. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Distinct binding of cetirizine enantiomers to human serum albumin and the human histamine receptor H1.
Journal of Computer-Aided Molecular Design ( IF 3.0 ) Pub Date : 2020-06-23 , DOI: 10.1007/s10822-020-00328-8
Almudena Perona 1, 2 , M Piedad Ros 1 , Alberto Mills 3 , Antonio Morreale 4 , Federico Gago 3
Affiliation  

Cetirizine, a major metabolite of hydroxyzine, became a marketed second-generation H1 antihistamine that is orally active and has a rapid onset of action, long duration of effects and a very good safety record at recommended doses. The approved drug is a racemic mixture of (S)-cetirizine and (R)-cetirizine, the latter being the levorotary enantiomer that also exists in the market as a third-generation, non-sedating and highly selective antihistamine. Both enantiomers bind tightly to the human histamine H1 receptor (hH1R) and behave as inverse agonists but the affinity and residence time of (R)-cetirizine are greater than those of (S)-cetirizine. In blood plasma, cetirizine exists in the zwitterionic form and more than 90% of the circulating drug is bound to human serum albumin (HSA), which acts as an inactive reservoir. Independent X-ray crystallographic work has solved the structure of the hH1R:doxepin complex and has identified two drug-binding sites for cetirizine on equine serum albumin (ESA). Given this background, we decided to model a membrane-embedded hH1R in complex with either (R)- or (S)-cetirizine and also the complexes of both ESA and HSA with these two enantiomeric drugs to analyze possible differences in binding modes between enantiomers and also among targets. The ensuing molecular dynamics simulations in explicit solvent and additional computational chemistry calculations provided structural and energetic information about all of these complexes that is normally beyond current experimental possibilities. Overall, we found very good agreement between our binding energy estimates and extant biochemical and pharmacological evidence. A much higher degree of solvent exposure in the cetirizine-binding site(s) of HSA and ESA relative to the more occluded orthosteric binding site in hH1R is translated into larger positional fluctuations and considerably lower affinities for these two nonspecific targets. Whereas it is demonstrated that the two known pockets in ESA provide enough stability for cetirizine binding, only one such site does so in HSA due to a number of amino acid replacements. At the histamine-binding site in hH1R, the distinct interactions established between the phenyl and chlorophenyl moieties of the two enantiomers with the amino acids lining up the pocket and between their free carboxylates and Lys179 in the second extracellular loop account for the improved pharmacological profile of (R)-cetirizine.



中文翻译:

西替利嗪对映体与人血清白蛋白和人组胺受体 H1 的不同结合。

西替利嗪是羟嗪的主要代谢物,成为上市的第二代 H 1抗组胺药,具有口服活性,起效快,作用持续时间长,推荐剂量下的安全记录非常好。批准的药物是 ( S )-西替利嗪和 ( R )-西替利嗪的外消旋混合物,后者是左旋对映异构体,也作为第三代、非镇静和高选择性抗组胺药存在于市场上。两种对映异构体都与人组胺 H 1受体 ( h H 1 R)紧密结合并表现为反向激动剂,但 ( R )-西替利嗪的亲和力和停留时间大于 ( S)-西替利嗪。在血浆中,西替利嗪以两性离子形式存在,超过 90% 的循环药物与人血清白蛋白 (HSA) 结合,后者充当非活性储库。独立的 X 射线晶体学工作已经解决了h H 1 R:doxepin 复合物的结构,并确定了马血清白蛋白 (ESA) 上西替利嗪的两个药物结合位点。鉴于此背景,我们决定对膜嵌入的h H 1 R 与 ( R )- 或 ( S)-西替利嗪以及 ESA 和 HSA 与这两种对映体药物的复合物,以分析对映体之间以及靶标之间结合模式的可能差异。随后在显式溶剂中进行的分子动力学模拟和额外的计算化学计算提供了所有这些复合物的结构和能量信息,这些信息通常超出了当前的实验可能性。总的来说,我们发现我们的结合能估计值与现有的生化和药理学证据之间非常吻合。相对于h H 1 中更封闭的正构结合位点,HSA 和 ESA 的西替利嗪结合位点中的溶剂暴露程度更高R 被转化为更大的位置波动和对这两个非特异性目标的相当低的亲和力。尽管已证明 ESA 中的两个已知口袋为西替利嗪结合提供了足够的稳定性,但由于大量氨基酸置换,在 HSA 中只有一个这样的位点这样做。在h H 1 R 中的组胺结合位点,两个对映异构体的苯基和氯苯基部分与排列在口袋中的氨基酸之间以及它们的游离羧酸盐和第二个细胞外环中的 Lys179 之间建立了明显的相互作用。 ( R )-西替利嗪的药理学特征。

更新日期:2020-06-23
down
wechat
bug