Jovanović Jelena Đorović, Antonijević Marko, Vojinović Radiša, Filipović Nenad D, Marković Zoran
Department of Science, Institute for Information Technologies, University of Kragujevac Jovana Cvijića bb 34000 Kragujevac Republic of Serbia
Faculty of Medical Sciences, University of Kragujevac Svetozara Markovića 69 34000 Kragujevc Republic of Serbia.
RSC Adv. 2022 Oct 17;12(46):29719-29726. doi: 10.1039/d2ra04226f.
Heart failure (HF) is a life-threatening condition that occurs when the heart cannot pump enough blood and oxygen to meet the body's needs. It affects mostly the elderly, commonly from the male population, especially those with obesity, diabetes, or some other chronic condition. It can be treated with different medications, and promising results were shown by a relatively new medicament called Entresto. Results obtained from molecular docking and molecular dynamics simulations to examine the inhibitory capacity of Entresto are presented in this study. Parameters obtained by the molecular docking simulations show that both parts of Entresto (sacubitril (SAC) and valsartan (VAL)) interact with targeted proteins, and inhibit their physiological function. Simulations of molecular dynamics revealed some interesting inhibitory patterns. SAC was discovered to produce structural alterations in neprilysin by binding to it, reducing neprilysin's physiological activity. In addition to blocking the active site, SAC binding causes the enzyme's structure to become less compact over time, causing changes in its biochemical characteristics and preventing the enzyme from performing its biological function. Similar to SAC, VAL also causes deviations in the structure of angiotensin receptors. The angiotensin receptor GPCR (G-protein-coupled receptors) is immersed in the lipid bilayer, and changes in the tertiary structure are only visible through RMSD and RMSF, not by examining . In this regard, MD simulations validated the results of molecular docking simulations, demonstrating that both SAC and VAL had inhibitory potential towards the neprilysin and angiotensin receptors, respectively.
心力衰竭（HF）是一种危及生命的病症，当心脏无法泵出足够的血液和氧气以满足身体需求时就会发生。它主要影响老年人，常见于男性群体，尤其是那些患有肥胖症、糖尿病或其他一些慢性疾病的人。它可以用不同的药物进行治疗，一种名为Entresto的相对较新的药物显示出了有前景的效果。本研究展示了通过分子对接和分子动力学模拟获得的结果，以检验Entresto的抑制能力。分子对接模拟获得的参数表明，Entresto的两个部分（沙库巴曲（SAC）和缬沙坦（VAL））都与目标蛋白相互作用，并抑制其生理功能。分子动力学模拟揭示了一些有趣的抑制模式。发现SAC通过与中性肽链内切酶结合，使其产生结构改变，降低了中性肽链内切酶的生理活性。除了阻断活性位点外，SAC的结合还导致该酶的结构随着时间的推移变得不那么紧凑，从而导致其生化特性发生变化，并阻止该酶发挥其生物学功能。与SAC类似，VAL也会导致血管紧张素受体结构的偏差。血管紧张素受体GPCR（G蛋白偶联受体）浸没在脂质双层中，三级结构的变化只能通过RMSD和RMSF观察到，而不是通过检查 。在这方面，分子动力学模拟验证了分子对接模拟的结果，表明SAC和VAL分别对中性肽链内切酶和血管紧张素受体具有抑制潜力。
