Nikfarjam Zahra, Rakhshi Reza, Zargari Farshid, Aalikhani Mahdi, Hasan-Abad Amin Moradi, Bazi Zahra
Department of Physical & Computational Chemistry, Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran.
Department of Medical Biotechnology, Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran.
Sci Rep. 2024 Dec 5;14(1):30349. doi: 10.1038/s41598-024-82065-8.
Inflammation is a defensive mechanism that safeguards the human body against detrimental stimuli. Within this intricate process, ADAM17, a zinc-dependent metalloprotease, emerges as an indispensable element, fostering the activation of diverse inflammatory and growth factors within the organism. Nonetheless, ADAM17 malfunctions can augment the rate of growth, inflammatory factors, and subsequent damage. Thus, in this study, we examined and repurposed drugs to suppress the activity of ADAM17. To this end, we employed bioinformatics techniques such as molecular docking, molecular dynamics, and pharmacokinetic studies. Five FDA-approved drugs including Raltegravir, Conivaptan, Paclitaxel, Saquinavir, and Venetoclax with the ability to impede the activity of the ADAM17 metalloenzyme were identified. Moreover, these drugs did not include strong zinc-binding functional groups when verified by the ACE functional group finder. However, further in silico analysis has indicated that Raltegravir demonstrates a commendable interaction with the active site amino acids and exhibits the most favorable pharmacokinetic properties compared to others. Considering the results of bioinformatics tools, it can be concluded that Raltegravir as an antiviral drug could be repurposed to prevent severe inflammatory response and tumorigenesis resulting from ADAM17 malfunction.
炎症是一种保护人体免受有害刺激的防御机制。在这个复杂的过程中，ADAM17（一种锌依赖性金属蛋白酶）成为不可或缺的元素，促进机体内多种炎症和生长因子的激活。然而，ADAM17功能异常会提高生长速率、增加炎症因子并导致后续损伤。因此，在本研究中，我们研究并重新利用药物来抑制ADAM17的活性。为此，我们采用了分子对接、分子动力学和药代动力学研究等生物信息学技术。确定了五种美国食品药品监督管理局（FDA）批准的药物，包括拉替拉韦、考尼伐坦、紫杉醇、沙奎那韦和维奈克拉，它们能够阻碍ADAM17金属酶的活性。此外，通过ACE官能团查找器验证时，这些药物不包含强锌结合官能团。然而，进一步的计算机模拟分析表明，拉替拉韦与活性位点氨基酸表现出良好的相互作用，并且与其他药物相比具有最有利的药代动力学性质。考虑到生物信息学工具的结果，可以得出结论，作为抗病毒药物的拉替拉韦可以重新用于预防由ADAM17功能异常导致的严重炎症反应和肿瘤发生。
