Over the years, phytochemical compounds have shown compelling evidences in exhibiting powerful antitumor properties. Moreover, due to the lack of safety and high cost of cancer therapies, opportunities are being sought out in these compounds as an alternative treatment modality. Therefore, in the present study, 1,574 compounds from NPACT library were examined to excavate potent and nontoxic anaplastic lymphoma kinase (ALK) inhibitors. Notably, two pharmacophore hypotheses (AAAHP and DDRRR) were generated using ligand-based and energy-based techniques, respectively, to eliminate false-positive prediction in database screening. Furthermore, molecular docking and Prime MM/GBSA analysis were performed on the screened compounds to examine inhibitory activity against ALK. The analysis revealed that the two hits, namely, NPACT00018 and NPACT01077, exhibited better docking scores, binding energies, and also ensured excellent drug-likeness properties than the reference compound, crizotinib. Finally, the results were subjected to molecular dynamics studies to gain insight into the stability of these compounds in the binding pocket of ALK protein. Indeed, the useful predictions generated by the present computational models are of immense importance and could further speed up the anticancer drug development in the near future.

中文翻译：

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从天然产物库中发现间变性淋巴瘤激酶抑制剂：一种整体的计算机方法

多年来，植物化学化合物在表现出强大的抗肿瘤特性方面已显示出令人信服的证据。此外，由于癌症治疗缺乏安全性和高成本，人们正在寻找这些化合物作为替代治疗方式的机会。因此，在本研究中，对 NPACT 库中的 1,574 种化合物进行了检测，以挖掘出有效且无毒的间变性淋巴瘤激酶 (ALK) 抑制剂。值得注意的是，分别使用基于配体和基于能量的技术生成了两个药效团假设（AAAHP 和 DDRRR），以消除数据库筛选中的假阳性预测。此外，对筛选的化合物进行分子对接和 Prime MM/GBSA 分析，以检查对 ALK 的抑制活性。分析显示，两个命中，即 NPACT00018 和 NPACT01077，与参考化合物克唑替尼相比，表现出更好的对接分数、结合能，并且还确保了出色的药物相似性。最后，对结果进行分子动力学研究，以深入了解这些化合物在 ALK 蛋白结合袋中的稳定性。事实上，目前的计算模型产生的有用预测非常重要，并且可以在不久的将来进一步加速抗癌药物的开发。