抗NUDT15变异体抗癌药物预防白血病患者白细胞减少副作用的比较评价

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Janakiraman V, Sudhan M, Khalaf F Alsharif, Ibrahim F Halawani, Shiek S S J Ahmed, Shankargouda Patil
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引用次数: 1

摘要

背景:人核苷酸三磷酸二磷酸酶(NUDT15)是参与白血病抗癌药物水解的重要蛋白之一。NUDT15的多态性显著影响水解活性,从而导致包括白细胞减少在内的副作用。与NUDT15蛋白亲和力较好且构象稳定的药物可能对白细胞减少患者有益。筛选了导致结构变异性的最常见NUDT15多态性及其与白血病的关系。收集选定的蛋白变异和抗癌药物结构。此外,在药物与NUDT15变体以及野生型之间进行了分子对接。最后,在100 ns的时间内进行分子动力学分析,以了解该蛋白与抗癌药物的稳定性。结果:从结构数据库中检索到NUDT15野生基因的三维结构、最常见的变异(Val18Ile、Arg139Cys和Arg139)和抗癌药物(硫唑嘌呤、巯基嘌呤和硫鸟嘌呤)。在分子对接上,抗癌药物对NUDT15结构的结合能在- 5.0 ~ - 5.9 kcal/mol之间。其中,偶氮嘌呤对野生型和变异型结构的亲和力最高(- 7.3 kcal/mol)。此外,分子动力学表明,所有分析的NUDT15与硫唑嘌呤的动力学轨迹是稳定的。结论:分子对接和动态模拟结果表明,硫唑嘌呤可能是NUDT15变异人群的首选抗癌药物,可以有效水解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients.

Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients.

Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients.

Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients.

Background: Human nucleotide triphosphate diphosphatase (NUDT15) is one of the essential proteins involved in the hydrolysis of anti-cancer drugs against leukemia. Polymorphisms in NUDT15 significantly affect the hydrolysis activity that leads to side effects, including leucopenia. Drugs having a better affinity with NUDT15 protein and contributing stable conformation may benefit patients from leucopenia. Most frequent NUDT15 polymorphisms causing structure variability and their association with leukemia were screened. The selected protein variants and anti-cancer drug structures were collected. Further, molecular docking was performed between drugs and NUDT15 variants along with the wild-type. Finally, molecular dynamics were executed for 100 ns to understand the stability of the protein with the anti-cancer drug based on molecular trajectories.

Results: Three-dimensional structures of NUDT15 wild, the most frequent variants (Val18Ile, Arg139Cys, and Arg139), and the anti-cancer drugs (azathioprine, mercaptopurine, and thioguanine) were selected and retrieved from structure databases. On molecular docking the binding energies of anti-cancer drugs against NUDT15 structures ranged from - 5.0 to - 5.9 kcal/mol. Among them, azathioprine showed the highest affinities (- 7.3 kcal/mol) for the wild and variant structures. Additionally, the molecular dynamics suggest all analyzed NUDT15 were stable with azathioprine based on the dynamic trajectories.

Conclusion: Our results suggest azathioprine could be the preferable anti-cancer drug for the population with NUDT15 variants that could effectively be hydrolyzed as evidenced by molecular docking and dynamic simulation.

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