Bansal Nisha, Parvez Mohammad Khalid, Babu M Arockia, Al-Dosari Mohammed S, Singh Thakur Gurjeet, Ali Nemat, Yadav Umesh, Bushi Ganesh, Gaidhane Abhay M
Gramothan Vidyapeeth Home Science Girls PG College, Sangaria, Rajasthan, India.
Department of Biotechnology, Graphic Era Deemed to be University, Dehradun, Uttarakhand, 248002, India.
Mol Divers. 2025 Jun 23. doi: 10.1007/s11030-025-11253-z.
Renin, an aspartyl protease enzyme, is a crucial part of the renin-angiotensin-aldosterone system (RAAS) that regulates blood pressure. However, numerous renin inhibitors, including Aliskiren, Zankiren, Enalkiren, Fasidotril, and Remikiren, are in the clinical arena of managing hypertension, but they are associated with numerous drawbacks. The important one includes modest efficacy in contrast to other antihypertensive agents, which reduces their use as monotherapy; secondly, the related side effects, including hyperkalemia and renal impairment. Thus, considering the unmet need to identify new renin inhibitors, we applied the drug repurposing technique on an 1880 US FDA-approved small molecules database. The research was achieved by performing the structure-based virtual screening (SBVD) on FDA-approved drugs, which was well supported by molecular docking, dynamics, and mechanics studies. This work identified Panobinostat as a possible lead renin inhibitor. The in vitro Elisa-based assay revealed Panobinostat has the potential to inhibit the renin enzyme at the half-maximal concentration (IC) of 201.27 nM, while standard renin inhibitor Aliskiren portrayed an IC of 162.22 nM. The comparable potency to clinical renin inhibitors presents this HDAC inhibitor as a dual-functioning ligand. The findings are significant and well correlated with the plethora of evidence suggesting the role of HDACs in regulating RAAS and cardiovascular functions via the post-translational level modulation of chromatins' structures and functions.
肾素是一种天冬氨酸蛋白酶，是调节血压的肾素 - 血管紧张素 - 醛固酮系统（RAAS）的关键组成部分。然而，包括阿利吉仑、赞奇仑、依那吉仑、法西多曲和瑞米吉仑在内的众多肾素抑制剂都处于高血压治疗的临床领域，但它们存在诸多缺点。其中重要的一点是与其他抗高血压药物相比疗效一般，这降低了它们作为单一疗法的使用；其次是相关的副作用，包括高钾血症和肾功能损害。因此，考虑到识别新型肾素抑制剂的未满足需求，我们对一个包含1880种美国食品药品监督管理局（FDA）批准的小分子的数据库应用了药物再利用技术。该研究通过对FDA批准的药物进行基于结构的虚拟筛选（SBVD）来实现，分子对接、动力学和力学研究为其提供了有力支持。这项工作确定帕比司他为一种可能的先导肾素抑制剂。基于酶联免疫吸附测定（ELISA）的体外试验表明，帕比司他在半最大浓度（IC）为201.27 nM时具有抑制肾素酶的潜力，而标准肾素抑制剂阿利吉仑的IC为162.22 nM。与临床肾素抑制剂相当的效力使这种组蛋白去乙酰化酶（HDAC）抑制剂成为一种具有双重功能的配体。这些发现意义重大，并且与大量证据密切相关，这些证据表明HDACs通过对染色质结构和功能的翻译后水平调节在调节RAAS和心血管功能中发挥作用。
