Rapalogues as hCES2A Inhibitors: In Vitro and In Silico Investigations
Rapalogues as hCES2A Inhibitors: In Vitro and In Silico Investigations
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Rapalogues 作为 hCES2A 抑制剂：体外和计算机研究
DOI：
10.1007/s13318-020-00659-9
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发表时间：
2020-11
影响因子：
1.9
通讯作者：
Zhang Li-Rong
中科院分区：
文献类型：
--
作者：
Shi Cheng-Cheng;Song Yun-Qing;He Rong-Jing;Guan Xiao-Qing;Song Li-Lin;Chen Shi-Tong;Sun Meng-Ru;Ge Guang-Bo;Zhang Li-Rong
雷帕霉素及其半合成类似物（雷帕霉素类似物）在临床上经常与其他处方药联合使用。虽然雷帕霉素类似物对细胞色素P450酶（CYP）的抑制作用已得到很好的研究，但雷帕霉素类似物对人酯酶的抑制潜力尚未研究。在此，6个市售的雷帕霉素类似物对人类esterases.MethodsThe抑制潜力和抑制机制的雷帕霉素，佐他莫司，替西罗莫司，依维莫司，吡美莫司和他克莫司对三种主要的酯酶，包括人类羧酸酯酶1（hCES1A），人类羧酸酯酶2（hCES2A）和丁酰胆碱酯酶（BuChE），使用同工酶特异性底物的抑制作用进行了测定。抑制动力学分析和对接模拟进行了调查rapalogues具有较强的hCES2A抑制potentis.ResultsZotarolimus和吡美莫司的抑制机制，显示出较强的抑制人hCES2A，但这些代理商不抑制hCES1A或BuChE。进一步研究表明，唑他莫司可强烈抑制活HepG2细胞中的细胞内hCES2A，估计IC 50值为4.09 µM。抑制动力学分析显示，佐他莫司以混合方式抑制hCES 2A催化的荧光素二乙酸酯水解，Ki值为1.61 µM。对接模拟结果表明，佐他莫司可与hCES 2A在两个区域的配体结合位点紧密结合，符合其混合抑制模式。这些药物可以作为开发更有效的hCES2A抑制剂的先导化合物，以调节hCES2A底物药物的药代动力学特征和毒性（如抗癌剂伊立替康）。图形摘要
Background and ObjectiveRapamycin and its semi-synthetic analogues (rapalogues) are frequently used in combination with other prescribed medications in clinical settings. Although the inhibitory effects of rapalogues on cytochrome P450 enzymes (CYPs) have been well examined, the inhibition potentials of rapalogues on human esterases have not been investigated. Herein, the inhibition potentials and inhibitory mechanisms of six marketed rapalogues on human esterases are investigated.MethodsThe inhibitory effects of six marketed rapalogues (rapamycin, zotarolimus, temsirolimus, everolimus, pimecrolimus and tacrolimus) on three major esterases, including human carboxylesterases 1 (hCES1A), human carboxylesterases 2 (hCES2A) and butyrylcholinesterase (BuChE), were assayed using isozyme-specific substrates. Inhibition kinetic analyses and docking simulations were performed to investigate the inhibitory mechanisms of the rapalogues with strong hCES2A inhibition potency.ResultsZotarolimus and pimecrolimus displayed strong inhibition of human hCES2A but these agents did not inhibit hCES1A or BuChE. Further investigation demonstrated that zotarolimus could strongly inhibit intracellular hCES2A in living HepG2 cells, with an estimated IC50value of 4.09 µM. Inhibition kinetic analyses revealed that zotarolimus inhibited hCES2A-catalyzed fluorescein diacetate hydrolysis in a mixed manner, with theKivalue of 1.61 µM. Docking simulations showed that zotarolimus could tightly bind on hCES2A at two district ligand-binding sites, consistent with its mixed inhibition mode.ConclusionOur findings demonstrate that several marketed rapalogues are potent and specific hCES2A inhibitors, and these agents can serve as leading compounds for the development of more efficacious hCES2A inhibitors to modulate the pharmacokinetic profiles and toxicity of hCES2A-substrate drugs (such as the anticancer agent irinotecan).Graphic Abstract
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影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
FEATHERSTONE, RM
影响因子：
3.9
作者：
P. Cai;R. Tsao;M. Ruppen
通讯作者：
P. Cai;R. Tsao;M. Ruppen
人类羧酸酯酶天然抑制剂的发现新进展
影响因子：
3.4
作者：
Wang Dan-Dan;Zou Li-Wei;Jin Qiang;Hou Jie;Ge Guang-Bo;Yang Ling
通讯作者：
Yang Ling
影响因子：
3.9
作者：
Godin, Stephen J.;Scollon, Edward J.;Ross, Matthew K.
通讯作者：
Ross, Matthew K.
DOI：
10.1124/jpet.106.111807
发表时间：
2006-12-01
影响因子：
3.5
作者：
Shi, Deshi;Yang, Jian;Yan, Bingfang
通讯作者：
Yan, Bingfang