神经生长因子 (NGF) 及其受体原肌球蛋白激酶 A 型受体激酶 (TrkA) 正在成为胶质母细胞瘤 (GBM) 治疗的重要靶点。 TrkA 是癌症生物标志物，主要参与肿瘤侵袭和迁移到附近正常组织的过程。然而，目前可用的 Trk 抑制剂对癌症患者表现出许多副作用，因此需要一类新型配体来调节 Trk 信号传导。在这里，我们利用了 651 个脑肿瘤数据集中的 TrkA (NTRK1) 表达的作用。 RNA序列分析发现NTRK1在GBM、复发性GBM以及少星形细胞瘤患者中过度表达。此外，TrkA 表达在 GBM 级别较高时趋于增加。设计了 TrkA 蛋白靶向腙衍生物 R48、R142 和 R234，并通过分子对接和动态模拟研究研究了它们的相互作用模式。配体的稳定性和结合评估表明，R48, 2 2-(2-(2-羟基-4-硝基苯基)亚肼基)-1-苯基丁烷-1,3-二酮是一种有效的配体，与 TrkA 的疏水残基 Ile 相互作用良好、Phe、Leu、Ala 和 Val。 R48-TrkA 表现出稳定的结合电位，平均 RMSD 值<0.8nm。 R48 遵循 Lipinski 的五法则，具有最佳的口服生物利用度，表明 R48 是一种具有药物相似特性的潜在化合物。体外分析还显示，R48对U87 GBM细胞表现出比TMZ更高的细胞毒作用，IC50值为68.99μM。它对表达非癌性 TrkA 的 MEF 细胞显示出最低百分比的细胞毒性。然而，进一步的 SiRNA 分析验证了 R48 的非特异性结合，因此需要进行结构改变，以开发用于 GBM 治疗的基于 R48 的 TrkA 抑制剂。版权所有 © 2023。由 Elsevier B.V 出版。

Nerve growth factor (NGF) and its receptor, tropomyosin kinase receptor kinase type A (TrkA) is emerging as an important target for Glioblastoma (GBM) treatment. TrkA is the cancer biomarker majorly involved in tumor invasion and migration into nearby normal tissue. However, currently, available Trk inhibitors exhibit many adverse effects in cancer patients, thus demanding a novel class of ligands to regulate Trk signaling. Here, we exploited the role of TrkA (NTRK1) expression from the 651 datasets of brain tumors. RNA sequence analysis identified overexpression of NTRK1 in GBM, recurrent GBM as well in Oligoastrocytoma patients. Also, TrkA expression tends to increase over the higher grades of GBM. TrkA protein targeting hydrazone derivatives, R48, R142, and R234, were designed and their mode of interaction was studied using molecular docking and dynamic simulation studies. Ligands' stability and binding assessment reveals R48, 2 2-(2-(2-hydroxy-4-nitrophenyl) hydrazineylidene)-1-phenylbutane-1,3-dione, as a potent ligand that interacts well with TrkA's hydrophobic residues, Ile, Phe, Leu, Ala, and Val. R48- TrkA exhibits stable binding potentials with an average RMSD value <0.8 nm. R48 obeyed Lipinski's rule of five and possessed the best oral bioavailability, suggesting R48 as a potential compound with drug-likeness properties. In-vitro analysis also revealed that R48 exhibited a higher cytotoxicity effect for U87 GBM cells than TMZ with the IC50 value of 68.99 μM. It showed the lowest percentage of cytotoxicity to the non-cancerous TrkA expressing MEF cells. However, further SiRNA analysis validates the non-specific binding of R48, necessitating structural alteration for the development of R48-based TrkA inhibitor for GBM therapeutics.Copyright © 2023. Published by Elsevier B.V.