Repurposing of existing FDA approved drugs for Neprilysin inhibition: an in-silico study,Journal of Molecular Structure

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Repurposing of existing FDA approved drugs for Neprilysin inhibition: an in-silico study
Journal of Molecular Structure ( IF 4.0 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.molstruc.2020.129073
Runali Sankhe ₁ , Ekta Rathi ₂ , Suman Manandhar ₁ , Avinash Kumar ₂ , Sreedhara Ranganath K Pai ₁ , Suvarna G Kini ₂ , Anoop Kishore ₁

Affiliation

Abstract Neprilysin (NEP) is a neutral endopeptidase with diverse physiological roles in the body. NEP's role in degradation of diverse classes of peptides such as amyloid beta, natriuretic peptide, substance P, angiotensin, endothelins, etc., is associated with pathologies of alzheimer's, kidney and heart disease, obesity, diabetes, and certain malignancies. Hence the functional inhibition of NEP in the above systems can be a good therapeutic target. In the present study, in-silico drug repurposing approach was used to identify NEP inhibitors. Molecular docking was carried out using GLIDE tool and 2934 drugs from the ZINC12 database were screened using high throughput virtual screening (HTVS) followed by standard precision (SP), and extra precision (XP) docking. Based on the XP docking score and ligand interaction, the top 8 hits were subjected to free ligand binding energy calculation, to filter out 4 hits (ZINC000000001427, ZINC000001533877, ZINC000000601283, and ZINC000003831594). Further, induced fit docking-standard precision (IFD-SP) and molecular dynamics (MD) studies were performed. The results obtained from MD +studies suggest that ZINC000000601283-NEP and ZINC000003831594-NEP complexes were most stable for 20ns simulation period as compared to ZINC000001533877-NEP and ZINC000000001427-NEP complexes. Interestingly, ZINC000000601283 and ZINC000003831594 showed similarity in binding with reported NEP inhibitor sacubitrilat. Findings from this study suggest that ZINC000000601283 and ZINC000003831594 may act as NEP inhibitors. In future studies, the role of ZINC000000601283 and ZINC000003831594 in NEP inhibition should be tested in biological systems to evaluate therapeutic effect in NEP associated pathological conditions.

中文翻译：

重新利用 FDA 批准的现有药物抑制脑啡肽酶：一项计算机内研究

摘要 Neprilysin (NEP) 是一种中性内肽酶，在体内具有多种生理作用。NEP 在降解不同种类的肽（例如β淀粉样蛋白、利钠肽、P 物质、血管紧张素、内皮素等）中的作用与阿尔茨海默病、肾脏和心脏病、肥胖症、糖尿病和某些恶性肿瘤的病理学有关。因此，上述系统中 NEP 的功能抑制可能是一个很好的治疗目标。在本研究中，计算机内药物再利用方法用于识别 NEP 抑制剂。使用 GLIDE 工具进行分子对接，并使用高通量虚拟筛选 (HTVS)、标准精密 (SP) 和超精密 (XP) 对接对 ZINC12 数据库中的 2934 种药物进行筛选。基于 XP 对接评分和配体相互作用，对前 8 个命中进行游离配体结合能计算，过滤出 4 个命中（ZINC000000001427、ZINC000001533877、ZINC000000601283 和 ZINC000003831594）。此外，还进行了诱导拟合对接标准精度 (IFD-SP) 和分子动力学 (MD) 研究。从 MD + 研究获得的结果表明，与 ZINC000001533877-NEP 和 ZINC000000001427-NEP 复合物相比，ZINC000000601283-NEP 和 ZINC000003831594-NEP 复合物在 20ns 模拟周期内最稳定。有趣的是，ZINC000000601283 和 ZINC000003831594 在与报道的 NEP 抑制剂 sacubitrilat 结合方面表现出相似性。这项研究的结果表明 ZINC000000601283 和 ZINC000003831594 可能充当 NEP 抑制剂。在未来的学习中，

更新日期：2021-01-01

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