当前位置: X-MOL 学术Chem. Phys. › 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.)
Tautomeric preferences of the cis and trans isomers of axitinib
Chemical Physics ( IF 2.3 ) Pub Date : 2018-04-12 , DOI: 10.1016/j.chemphys.2018.04.006
M. Saeed Mirzaei , Avat Arman Taherpour

The tautomeric preferences of axitinib, a potent anticancer drug, as tyrosine kinase inhibitor have been investigated using quantum chemical calculations and docking methods. The energy differences between the two tautomers of trans-isomer are around 4 and 3 kcal mol−1 in vacuo and water, respectively, and for its cis-isomer (major photochemical isomerization product) this equilibrium reversed completely in favour of the second tautomer (not considered previously), which is about 7–8 kcal mol−1 more stable in both gas and aqueous media. The results indicate a very high activation energy for proton exchange for both [1,2] and [1,5] H-shift (around 50 kcal mol−1) in the gas phase, but inclusion of protic solvents (e.g. water) decrease this barrier to around 14 and 35 kcal mol−1 for the both hydrogen shift processes, respectively. In order to have better insight about the electronic structure of axitinib tautomers, the NBO, HOMO-LUMO, NICS and molecular electrostatic potential surfaces (MESP) calculations have been carried out. Docking investigations on the two more stable tautomers revealed that binding of the trans isomer of tautomer I to the active site of the receptor is the most favourable in the terms of energy and structure. This more stability could be attributed to the more hydrogen bonding of this tautomer with the protein residues in comparison to the second tautomer.



中文翻译:

阿昔替尼顺式反式异构体的互变异构偏好

已经使用量子化学计算和对接方法研究了有效的抗癌药阿昔替尼作为酪氨酸激酶抑制剂的互变异构偏好。反式异构体的两个互变异构体在真空和水中的能量差分别约为4和3 kcal mol -1,对于其顺式异构体(主要的光化学异构化产物),该平衡完全逆转,有利于第二个互变异构体(以前没有考虑过),在气体和水介质中都稳定约7–8 kcal mol -1。结果表明,对于[1,2]和[1,5] H位移,质子交换都具有很高的活化能(约50 kcal mol -1)在气相中,但是对于两个氢转移过程,包含质子溶剂(例如水)分别将这种势垒减小至约14和35kcal mol -1。为了更好地了解阿西替尼互变异构体的电子结构,已进行了NBO,HOMO-LUMO,NICS和分子静电势表面(MESP)计算。对两种更稳定的互变异构体的对接研究表明,就能量和结构而言,互变异构体I的反式异构体与受体活性位点的结合是最有利的。与第二互变异构体相比,该更高的稳定性可归因于该互变异构体与蛋白质残基的更多氢键结合。

更新日期:2018-04-17
down
wechat
bug