Ahmed Shanzay, John Peter, Paracha Rehan Zafar, Bhatti Attya, Guma Monica
Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan.
School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan.
Life (Basel). 2022 Jul 29;12(8):1148. doi: 10.3390/life12081148.
Enhancement of glycolysis and glutaminolysis are the two most common modalities associated with metabolic reprogramming in rheumatoid arthritis (RA). This enhancement is concomitant to the upregulation of hexokinase 2 (HK2) and glutaminase 1 (GLS1). Hence, the current study was undertaken to identify potential phytobiological inhibitors against HK2 and GLS1, from , an indigenous ethnomedicinal plant found in Pakistan, using computational analysis. Phytobiologics from were assessed for their ability to co-inhibit HK2 and GLS1 via molecular docking and molecular dynamics simulations. The results underscored seven phytobiologics with promising binding affinities for both HK2 and GLS1. Molecular dynamics simulations further elucidated that all seven identified phytobiologics inhibited HK2 by forming stable complexes but only five amongst the seven had the potential to form stable complexes with GLS1 in real time, thereby implying the potential of co-inhibition for these five compounds. Compound 28MS exhibited an equally strong binding profile for both HK2 (-8.19 kcal/mol) and GLS1 (-8.99 kcal/mol). Furthermore, it exhibited a similar trend in stability during simulation for both targets. Our results serve as a primer for a more lucid understanding towards co-inhibition of HK2 and GLS1 using multiple computational approaches. The identified phytobiologics should undergo and validation to corroborate their therapeutic potential in RA.
糖酵解和谷氨酰胺分解增强是类风湿性关节炎（RA）中与代谢重编程相关的两种最常见方式。这种增强伴随着己糖激酶2（HK2）和谷氨酰胺酶1（GLS1）的上调。因此，本研究旨在通过计算分析，从巴基斯坦本土的一种民族药用植物中鉴定出针对HK2和GLS1的潜在植物生物抑制剂。通过分子对接和分子动力学模拟评估了该植物的植物生物制剂对HK2和GLS1的共抑制能力。结果强调了七种对HK2和GLS1均具有良好结合亲和力的植物生物制剂。分子动力学模拟进一步阐明，所有七种鉴定出的植物生物制剂均通过形成稳定复合物来抑制HK2，但七种中只有五种有可能与GLS1实时形成稳定复合物，这意味着这五种化合物具有共抑制潜力。化合物28MS对HK2（-8.19 kcal/mol）和GLS1（-8.99 kcal/mol）均表现出同样强的结合特征。此外，它在两个靶点的模拟过程中稳定性呈现出相似趋势。我们的结果为使用多种计算方法更清晰地理解HK2和GLS1的共抑制作用提供了一个开端。所鉴定出的植物生物制剂应经过体外和体内验证，以证实它们在类风湿性关节炎中的治疗潜力。
