Adnan Mohd, Koli Saadgee, Mohammad Taj, Siddiqui Arif Jamal, Patel Mitesh, Alshammari Nawaf, Bardakci Fevzi, Elasbali Abdelbaset Mohamed, Hassan Md Imtaiyaz
Department of Biology, College of Science, University of Ha'il, Ha'il, Saudi Arabia.
Molecular Diagnostics and Personalized Therapeutics Unit, University of Ha'il, Ha'il, Saudi Arabia.
OMICS. 2022 Aug;26(8):461-470. doi: 10.1089/omi.2022.0067. Epub 2022 Aug 4.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase molecular target with broad importance for drug discovery, especially in the field of cancer therapeutics. ALK belongs to the insulin receptor superfamily that is involved in various malignancies, including non-small cell lung cancer, anaplastic large cell lymphoma, and neuroblastoma. ALK has been shown to play a role in cancer progression and metastasis, making it one of the prime targets to develop novel anticancer therapeutics. In this context, natural compounds can be an important resource to unravel novel ALK inhibitors. In this study, we report a structure-based virtual screening of natural compounds from the ZINC database, with an eye to potential inhibitors of ALK. Molecular docking was performed on a natural compound library, and top hits holding good binding affinity, docking score, and specificity toward ALK were selected. The hits were further evaluated based on the PAINS (pan-assay interference compounds) filter, ADMET (absorption, distribution, metabolism, excretion, toxicity) properties, PASS (prediction of activity spectra for substances) analysis, and two-dimensional interaction of protein-ligand complexes. Importantly, two natural compounds (ZINC03845566 and ZINC03999625) were identified as potential candidates for ALK, having appreciable affinity and specificity toward the ALK binding pocket and depicting drug-like properties as predicted from ADMET analysis and their physicochemical parameters. An all-atom molecular dynamics simulation for 100 ns on ALK promised stable ALK-ligand complexes. Hence, we conclude that ZINC03845566 and ZINC03999625 can act as potential ALK inhibitors against cancers where ALK plays a role, for example, in lung cancer, among others. All in all, these findings inform future discovery and translational research for ALK inhibitors as anticancer drugs.
间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶分子靶点，在药物发现中具有广泛的重要性，尤其是在癌症治疗领域。ALK属于胰岛素受体超家族，涉及多种恶性肿瘤，包括非小细胞肺癌、间变性大细胞淋巴瘤和神经母细胞瘤。ALK已被证明在癌症进展和转移中起作用，使其成为开发新型抗癌疗法的主要靶点之一。在此背景下，天然化合物可能是发现新型ALK抑制剂的重要资源。在本研究中，我们报告了基于结构的从ZINC数据库中对天然化合物的虚拟筛选，旨在寻找潜在的ALK抑制剂。对一个天然化合物库进行了分子对接，并选择了对ALK具有良好结合亲和力、对接分数和特异性的顶级命中物。基于PAINS（泛测定干扰化合物）筛选、ADMET（吸收、分布、代谢、排泄、毒性）性质、PASS（物质活性谱预测）分析以及蛋白质-配体复合物的二维相互作用对命中物进行了进一步评估。重要的是，两种天然化合物（ZINC03845566和ZINC03999625）被鉴定为ALK的潜在候选物，它们对ALK结合口袋具有可观的亲和力和特异性，并如ADMET分析及其物理化学参数所预测的那样表现出类药物性质。对ALK进行了100纳秒的全原子分子动力学模拟，结果显示ALK-配体复合物稳定。因此，我们得出结论，ZINC03845566和ZINC03999625可作为潜在的ALK抑制剂，用于治疗ALK起作用的癌症，例如肺癌等。总之，这些发现为未来将ALK抑制剂作为抗癌药物的发现和转化研究提供了信息。
