Alshammari Saud O, Alshammari Qamar A
Department of Pharmacognosy and Alternative Medicine, College of Pharmacy, Northern Border University, Rafha, 76321, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, Northern Border University, Rafha, 76321, Saudi Arabia.
Mol Divers. 2025 Jun;29(3):1969-1982. doi: 10.1007/s11030-024-10953-2. Epub 2024 Aug 8.
Anaplastic lymphoma kinase (ALK)-driven lung cancer represents a critical therapeutic target, demanding innovative approaches for the identification of effective inhibitors. Anaplastic lymphoma kinase (ALK), a key protein involved in the pathogenesis of ALK-driven lung cancers, has been the focus of extensive drug discovery efforts. This study employed a comprehensive computational drug discovery approach, integrating virtual screening with the Lipinski filter, re-docking, molecular dynamics (MD) simulations, and free energy calculations to identify potential inhibitors from a natural compound library. Utilizing the MTiOpenScreen web server, we screened for compounds that exhibit favorable interactions with ALK, resulting in 1227 compounds with virtual screening scores ranging from - 10.2 to - 3.7 kcal/mol. Subsequent re-docking of three selected compounds (ZINC000059779788, ZINC000043552589, and ZINC000003594862) and one reference compound against ALK yielded docking scores - 10.4, - 10.2, - 10.2, and - 10.1 kcal/mol, respectively. These compounds demonstrated promising interactions with ALK, suggesting potential inhibitory effects. Advanced analyses, including MD simulation and binding free energy calculations, further supported the potential efficacy of these compounds. MD simulations, particularly the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses, revealed that compounds ZINC000059779788 and ZINC000003594862 achieved better stability compared to compound ZINC000043552589. These stable conformations suggest effective binding over time. Free energy calculations using the MM/GBSA method showed that ZINC000059779788 had the most favorable binding energy, indicating a strong and stable interaction with the ALK protein. The promising computational findings from this study emphasize the necessity for additional experimental testing to verify the therapeutic efficacy of these natural compounds for treating lung cancers.
间变性淋巴瘤激酶（ALK）驱动的肺癌是一个关键的治疗靶点，需要创新方法来鉴定有效的抑制剂。间变性淋巴瘤激酶（ALK）是ALK驱动的肺癌发病机制中的关键蛋白，一直是广泛药物研发工作的重点。本研究采用了一种全面的计算药物研发方法，将虚拟筛选与Lipinski过滤器、重新对接、分子动力学（MD）模拟以及自由能计算相结合，从天然化合物库中鉴定潜在抑制剂。利用MTiOpenScreen网络服务器，我们筛选出与ALK表现出良好相互作用的化合物，得到1227种虚拟筛选分数在-10.2至-3.7千卡/摩尔之间的化合物。随后，对三种选定化合物（ZINC000059779788、ZINC000043552589和ZINC000003594862）以及一种参考化合物与ALK进行重新对接，得到的对接分数分别为-10.4、-10.2、-10.2和-10.1千卡/摩尔。这些化合物与ALK表现出有前景的相互作用，表明具有潜在抑制作用。包括MD模拟和结合自由能计算在内的进一步分析，进一步支持了这些化合物的潜在疗效。MD模拟，特别是均方根偏差（RMSD）和均方根波动（RMSF）分析表明，与化合物ZINC000043552589相比，化合物ZINC000059779788和ZINC000003594862具有更好的稳定性。这些稳定构象表明随着时间推移具有有效的结合。使用MM/GBSA方法进行的自由能计算表明，ZINC000059779788具有最有利的结合能，表明与ALK蛋白有强烈且稳定的相互作用。本研究有前景的计算结果强调了进行额外实验测试以验证这些天然化合物治疗肺癌疗效的必要性。
