V Janakiraman, M Sudhan, Alsharif Khalaf F, Halawani Ibrahim F, Ahmed Shiek S S J, Patil Shankargouda
Drug Discovery and Multi-Omics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam-603103, Tamil Nadu, India.
Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia.
J Genet Eng Biotechnol. 2023 Aug 9;21(1):82. doi: 10.1186/s43141-023-00538-1.
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.
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.
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.
人核苷酸三磷酸二磷酸酶（NUDT15）是参与抗癌药物对白血病水解作用的必需蛋白质之一。NUDT15基因多态性显著影响水解活性，进而导致包括白细胞减少在内的副作用。与NUDT15蛋白具有更好亲和力并有助于稳定构象的药物可能使患者免受白细胞减少之苦。筛选了导致结构变异的最常见NUDT15多态性及其与白血病的关联。收集了选定的蛋白质变体和抗癌药物结构。此外，对药物与NUDT15变体以及野生型进行了分子对接。最后，基于分子轨迹进行了100纳秒的分子动力学模拟，以了解蛋白质与抗癌药物结合的稳定性。
从结构数据库中选择并检索了NUDT15野生型、最常见变体（Val18Ile、Arg139Cys和Arg139）以及抗癌药物（硫唑嘌呤、巯嘌呤和硫鸟嘌呤）的三维结构。通过分子对接，抗癌药物与NUDT15结构的结合能范围为-5.0至-5.9千卡/摩尔。其中，硫唑嘌呤对野生型和变体结构显示出最高亲和力（-7.3千卡/摩尔）。此外，分子动力学模拟表明，基于动力学轨迹，所有分析的NUDT15与硫唑嘌呤结合时都是稳定的。
我们的结果表明，对于携带NUDT15变体的人群，硫唑嘌呤可能是更合适的抗癌药物，分子对接和动力学模拟表明其可被有效水解。
