Rodrigues Fiona C, Hari Gangadhar, Pai K S R, Suresh Akhil, Nayak Usha Y, Anilkumar N V, Thakur Goutam
Department of Biomedical Engineering, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576 104 India.
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576 104 India.
3 Biotech. 2021 Dec;11(12):506. doi: 10.1007/s13205-021-03051-9. Epub 2021 Nov 22.
The human Abl kinases comprise a family of proteins that are known to be key stimulus drivers in the signaling pathways modulating cell growth, cell survival, cell adhesion, and apoptosis. Recent collative studies have indicated the role of activation of Abl and Abl-related genes in solid tumors; further terming the Abl kinases as molecular switches which promote proliferation, tumorigenesis, and metastasis. The up-regulated Abl-kinase expression in colorectal cancer (CRC) and the role of Abl tyrosine kinase activity in the Matrigel invasion of CRC cells have cemented its significance in CRC advancement. Therefore, the requisite of identifying small molecules which serve as Abl selective inhibitors and designing anti-Abl therapies, particularly for CRC tumors, has driven this study. Curcumin has been touted as an effective inhibitor of cancer cells; however, it is limited by its physicochemical inadequacies. Hence, we have studied the behavior of heterocyclic derivatives of curcumin via computational tools such as pharmacophore-based virtual screening, molecular docking, free-energy binding, and ADME profiling. The most actively docked molecule, 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide, was comparatively evaluated against Curcumin via molecular dynamics simulation using Desmond, Schrödinger. The study exhibited the improved stability of the derivative as compared to Curcumin in the tested protein pocket and displayed the interaction bonds with the contacted key amino acids. To further establish the claim, the derivatives were synthesized via the mechanism of cyclization of Curcumin and screened in vitro using SRB assay against human CRC cell line, HCT 116. The active derivative indicated an IC value of 5.85 µM, which was sevenfold lower as compared to Curcumin's IC of 35.40 µM. Hence, the results base the potential role of the curcumin derivative in modulating Abl-kinase activity and in turn may have potential therapeutic value as a lead for CRC therapy.
The online version contains supplementary material available at 10.1007/s13205-021-03051-9.
人类Abl激酶是一类蛋白质，已知其在调节细胞生长、细胞存活、细胞黏附和细胞凋亡的信号通路中是关键的刺激驱动因子。最近的整理研究表明Abl及Abl相关基因的激活在实体瘤中的作用；进一步将Abl激酶称为促进增殖、肿瘤发生和转移的分子开关。结直肠癌（CRC）中Abl激酶表达上调以及Abl酪氨酸激酶活性在CRC细胞基质胶侵袭中的作用巩固了其在CRC进展中的重要性。因此，识别作为Abl选择性抑制剂的小分子并设计抗Abl疗法，特别是针对CRC肿瘤的疗法，推动了本研究。姜黄素被誉为癌细胞的有效抑制剂；然而，它受到其物理化学缺陷的限制。因此，我们通过基于药效团的虚拟筛选、分子对接、自由能结合和ADME分析等计算工具研究了姜黄素杂环衍生物的行为。使用薛定谔公司的Desmond通过分子动力学模拟将对接最活跃的分子3,5-双（4-羟基-3-甲基苯乙烯基）-1H-吡唑-1-甲酰胺与姜黄素进行了比较评估。该研究表明该衍生物在测试的蛋白口袋中与姜黄素相比稳定性有所提高，并显示出与接触的关键氨基酸的相互作用键。为了进一步证实这一说法，通过姜黄素环化机制合成了这些衍生物，并使用SRB测定法在体外针对人CRC细胞系HCT 116进行了筛选。活性衍生物的IC值为5.85 μM，与姜黄素的IC值35.40 μM相比低七倍。因此，结果表明姜黄素衍生物在调节Abl激酶活性方面的潜在作用，进而可能作为CRC治疗的先导具有潜在的治疗价值。
在线版本包含可在10.1007/s13205-021-03051-9获取的补充材料。
