Fragment Molecular Orbital Study of the Interaction between Sarco/Endoplasmic Reticulum Ca2+-ATPase and its Inhibitor Thapsigargin toward Anti-Malarial Development
Fragment Molecular Orbital Study of the Interaction between Sarco/Endoplasmic Reticulum Ca2+-ATPase and its Inhibitor Thapsigargin toward Anti-Malarial Development
复制标题
DOI：
10.1021/acs.jpcb.8b04509
复制
发表时间：
2018-08-23
影响因子：
3.3
通讯作者：
Yahata, Kazuhide
中科院分区：
文献类型：
--
作者：
Ishikawa, Takeshi;Mizuta, Satoshi;Yahata, Kazuhide
恶性疟疾的病原体恶性疟原虫对毒胡萝卜素 (TG) 不敏感，而毒胡萝卜素是一种众所周知的人类肌肉/内质网 Ca2+-ATP 酶 (SERCA) 抑制剂。为了了解造成灵敏度差异的关键因素，通过片段分子轨道（FMO）方法分析了TG和每个SERCA的分子相互作用。虽然相互作用能的主要组成部分是非极性相互作用，但分子相互作用的主要差异来自极性相互作用，即与TG的羟基的氢键相互作用。此外，我们通过测量合成的 TG 衍生物的抑制活性成功证实了这些 FMO 计算结果。我们的计算和实验表明，通过用另一个官能团取代TG的羟基，可以逆转TG对人和恶性疟原虫SERCA的敏感性。这项研究为开发针对恶性疟原虫 SERCA 的抗疟化合物提供了重要信息。
Plasmodium falciparum, the causative agent of malignant malaria, is insensitive to thapsigargin (TG), a well-known inhibitor of the human sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). To understand the key factor causing the difference of the sensitivity, the molecular interaction of TG and each SERCA was analyzed by the fragment molecular orbital (FMO) method. While the major component of the interaction energy was the nonpolar interaction, the major difference in the molecular interaction arose from the polar interaction, namely, the hydrogen bonding interaction with a hydroxyl group of TG. Additionally, we successfully confirmed these FMO calculation results by measuring the inhibitory activity of a synthesized TG derivative. Our calculations and experiments indicated that, by replacing the hydroxyl group of TG with another functional group, the sensitivities of TG to human and P. falciparum SERCAs can be reversed. This study provides important information to develop antimalarial compounds targeting P. falciparum SERCA.