指导医学治疗(GDMT)已成为欧洲心脏病学会(ESC)推荐的射血分数降低的心力衰竭患者的标准药物治疗。然而,GDMT患者可能具有肾毒性作为不良反应.我们利用了多种系统生物学工具,如ADVER-Pred,基因富集分析,分子对接,分子动力学模拟,和MMPBSA分析来预测GDMT的选定组合如何引起肾毒性的可能分子机制。根据ACC/AHA/ESC指南,我们将药物分类为1类,包括β受体阻滞剂(BB),血管紧张素受体阻滞剂(ARB),和钠-葡萄糖协同转运蛋白-2抑制剂(SGLT2I),第2类包括BB,SGLT2I,和血管紧张素受体-脑啡肽抑制剂(ARNI),第3类包括BB,SGLT2I,和血管紧张素转换酶(ACE)抑制剂。富集分析预测2类药物具有参与肾毒性发展的最高数量的蛋白质,即79.41%。目标HBA1,CBR1,ATG5和SLC6A3是边缘计数为7的最高中心基因,其次是边缘计数为6的GPX1。分子对接研究显示坎地沙坦-SLC6A3具有-10.2kcal/mol的最高结合亲和力。此外,模拟研究表明,依帕格列净-CBR1具有最高的稳定性,其次是坎地沙坦-ATG5。β受体阻滞剂的组合,ARBs,预计SGLT2I可能具有肾毒性,这可能是由于HBA1,CBR1,ATG5和GPX1的调节。总之,坎地沙坦和依帕格列净最有可能通过调节HBA1,CBR1,ATG5和GPX1引起肾毒性。由RamaswamyH.Sarma沟通。
预测GDMT药物具有肾毒性作为2类药物BB的不利影响,SGLT2I,和ARNI被评估为具有最高数量的蛋白质参与肾毒性的发展,这可能是通过调节HBA1,CBR1,ATG5和GPX1。坎地沙坦和依帕列净最可能引起肾毒性。
Guideline Directed Medical Therapy (GDMT) has been the standard pharmacotherapy for the treatment of Heart Failure patients with reduced Ejection Fraction (HFrEF) recommended by the European Society of Cardiology (ESC). However, patients on GDMT are likely to possess
nephrotoxicity as an adverse effect. We utilized multiple system biology tools like ADVER-Pred, gene enrichment analysis, molecular docking, molecular dynamic simulations, and MMPBSA analysis to predict a possible molecular mechanism of how selected combinations of GDMT may cause nephrotoxicity. As per the ACC/AHA/ESC
guidelines, we categorized the drugs as category 1 including β-blockers (BB), angiotensin receptor blockers (ARB), and sodium-glucose cotransporter-2 inhibitors (SGLT2I), category 2 includes BB\'s, SGLT2I, and angiotensin receptor-neprilysin inhibitors (ARNI), and category 3 includes BB\'s, SGLT2I, and angiotensin-converting enzyme (ACE) inhibitors. Enrichment analysis predicted category 2 drugs to possess the highest number of proteins to be involved in the development of nephrotoxicity i.e. 79.41%. The targets HBA1, CBR1, ATG5, and SLC6A3 were the top hub genes with an edge count of 7 followed by GPX1 with an edge count of 6. Molecular docking studies revealed candesartan-SLC6A3 to possess the highest binding affinity of -10.2 kcal/mol. In addition, simulation studies displayed empagliflozin-CBR1 to possess the highest stability followed by candesartan-ATG5. A combination of β-blockers, ARBs, and SGLT2I are predicted to likely possess
nephrotoxicity which may be due to the modulation of HBA1, CBR1, ATG5, and GPX1. In conclusion, candesartan and empagliflozin are most likely to cause
nephrotoxicity via the modulation of HBA1, CBR1, ATG5, and GPX1.Communicated by Ramaswamy H. Sarma.
GDMT drugs were predicted to possess nephrotoxicity as an adverse effectCategory 2 drugs BB’s, SGLT2I, and ARNI were assessed to possess highest number of proteins to be involved in the development of nephrotoxicity which may be by modulating HBA1, CBR1, ATG5, and GPX1.Candesartan and empagliflozin are most likely to cause nephrotoxicity.