Shahin Rand, Mansi Iman, Swellmeen Lubna, Alwidyan Tahani, Al-Hashimi Nabil, Al-Qarar'h Yaser, Shaheen Omar
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical sciences, Hashemite University, Zarqa, Jordan.
Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical sciences, Hashemite University, Zarqa, Jordan.
J Mol Graph Model. 2018 Mar;80:327-352. doi: 10.1016/j.jmgm.2018.01.004. Epub 2018 Jan 13.
Targeting tropomycin kinase A (TrkA) by small molecule inhibitors is considered as a promising strategy for treating several human cancers. To achieve this goal, a ligand based QSAR model was applied using the Discovery studio 4.5 (DS 4.5). Hence, a total list of 161 TrkA inhibitors was investigated. The TrkA inhibitors were extensively explored to detect their optimal physicochemical properties and pharmacophoric binding modes, which were converted into numeric descriptors and allowed to compete within the context of the Genetic Function Algorithm (GFA) approximations to find the subset of terms that correlates best with the activity. The resulted successful QSAR equation had statistical criteria of (r=0.67, r=0.61 r against 32 external test inhibitors=0.50). Afterwards, the most successful pharmacophore: HypoB-T5-3, was used to screen compounds within the National Cancer institute (NCI) database. Only 41 compounds were retrieved and 21 of them exhibited anti-TrkA activity. The most potent hit had an IC value of 2.4μM. Later, upon docking the active hits into the TrkA binding pocket, important interactions were revealed including hydrogen bonding with the amino acids Asp668 and Lys544 in addition to the cation-π interactions with the sidechain of Arg559.
通过小分子抑制剂靶向原肌球蛋白激酶A（TrkA）被认为是治疗多种人类癌症的一种有前景的策略。为实现这一目标，使用Discovery studio 4.5（DS 4.5）应用了基于配体的定量构效关系（QSAR）模型。因此，对总共161种TrkA抑制剂进行了研究。对TrkA抑制剂进行了广泛探索，以检测其最佳物理化学性质和药效团结合模式，这些性质和模式被转化为数字描述符，并在遗传函数算法（GFA）近似的背景下进行竞争，以找到与活性最相关的项子集。所得成功的QSAR方程具有统计学标准（r = 0.67，r = 0.61，与32种外部测试抑制剂的r = 0.50）。之后，最成功的药效团HypoB-T5-3被用于筛选美国国立癌症研究所（NCI）数据库中的化合物。仅检索到41种化合物，其中21种表现出抗TrkA活性。最有效的命中化合物的IC值为2.4μM。后来，将活性命中化合物对接至TrkA结合口袋时，揭示了重要的相互作用，包括与氨基酸Asp668和Lys544的氢键作用以及与Arg559侧链的阳离子-π相互作用。
