Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
Department of Bioinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
J Biomol Struct Dyn. 2024 Feb-Mar;42(3):1469-1484. doi: 10.1080/07391102.2023.2217923. Epub 2023 Jun 5.
Drug repurposing is proved to be a groundbreaking concept in the field of cancer research, accelerating the pace of drug discovery by investigating the anti-cancer activity of the already approved drugs. On the other hand, it got highly benefitted from the advancement in the tools and techniques, which are used to build up the initial "proof of concept" based on the drug-target interaction. Acalabrutinib (ACL) is a well-known drug for the treatment of hematological malignancies. But, the therapeutic ability of ACL against solid tumors is still unexplored. Thereby, the activity of ACL on breast cancer and lung cancer was evaluated utilizing different computational methods. A series of proteins such as VEGFR1, ALK, BCL2, CXCR-4, mTOR, AKT, PI3K, HER-2, and Estrogen receptors were selected based on their involvement in the progression of the breast as well as lung cancer. A multi-level computational study starting from protein-ligand docking to molecular dynamic (MD) simulations were performed to detect the binding potential of ACL towards the selected proteins. Results of the study led to the identification of ACL as a ligand that showed a high docking score and binding energy with HER-2, mTOR, and VEGFR-1 successively. Whereas, the MD simulations study has also shown good docked complex stability of ACL with HER2 and VEGFR1. Our findings suggest that interaction with those receptors can lead to preventive action on both breast and lung cancer, thus it can be concluded that ACL could be a potential molecule for the same purpose.Communicated by Ramaswamy H. Sarma.
药物重定位被证明是癌症研究领域的一个开创性概念，通过研究已批准药物的抗癌活性，加速了药物发现的步伐。另一方面，它得益于工具和技术的进步，这些工具和技术用于根据药物-靶标相互作用建立最初的“概念验证”。阿卡鲁替尼 (ACL) 是一种用于治疗血液系统恶性肿瘤的知名药物。但是，ACL 对实体瘤的治疗能力仍未得到探索。因此，利用不同的计算方法评估了 ACL 对乳腺癌和肺癌的活性。选择了一系列蛋白质，如 VEGFR1、ALK、BCL2、CXCR-4、mTOR、AKT、PI3K、HER-2 和雌激素受体，因为它们参与了乳腺癌和肺癌的进展。从蛋白配体对接开始，进行了一系列多层次的计算研究，包括分子动力学 (MD) 模拟，以检测 ACL 对所选蛋白质的结合潜力。研究结果表明，ACL 是一种配体，它与 HER-2、mTOR 和 VEGFR-1 依次显示出高对接分数和结合能。而 MD 模拟研究也表明 ACL 与 HER2 和 VEGFR1 的结合复合物具有良好的稳定性。我们的研究结果表明，与这些受体的相互作用可能导致对乳腺癌和肺癌的预防作用，因此可以得出结论，ACL 可能是具有相同目的的潜在分子。Ramashwamy H. Sarma 通讯。
