尽管在治疗和诊断方面取得了相当大的进步,脑肿瘤仍然是全球公共卫生关注的问题。在所有脑肿瘤中,80%是由于胶质母细胞瘤。一旦诊断患有胶质母细胞瘤的患者的平均存活率为15个月。最近,肽酶的作用,尤其是Neprilysin,中性内肽酶,因其在肿瘤生长调节中的作用而受到关注。Neprilysin的表达与包括GBM在内的多种肿瘤呈正相关,NEP蛋白的表达降低与多种肿瘤的发病机制有关。NEP蛋白下调的主要原因之一是组蛋白去乙酰化酶(HDAC)的作用,尤其是HDAC1。此外,研究报道,HDAC1水平升高是下调NEP基因表达的原因.因此,HDAC1抑制可以是提高NEP水平的良好目标,这可能是GBM的良好治疗方法。这项研究利用了计算药物再利用工具,SchrodingerMaestro从ZINC15数据库中鉴定HDAC1抑制剂。通过分子对接从ZINC15数据库中筛选了1379种FDA批准的药物。基于对接评分和配体-蛋白质相互作用,选择前10个分子,然后对其进行结合能计算和分子动力学(MD)模拟。来自MD模拟的三种最具活性的药物-ZINC22010649(Panobinostat),ZINC4392649(Tasimelteon)和ZINC1673(美法伦),使用蛋白质印迹分析在C6和U87MG胶质母细胞瘤细胞上测试细胞毒性和HDAC1蛋白水平。在这三种药物中,Panobinostat表现出有效的细胞毒性作用,并显示HDAC1蛋白水平的显着降低。由RamaswamyH.Sarma沟通。
Despite considerable improvement in therapy and diagnosis, brain tumors remain a global public health concern. Among all brain tumors, 80% are due to Glioblastoma. The average survival rate of a patient once diagnosed with glioblastoma is 15 months. Lately, the role of peptidase enzymes, especially Neprilysin, a neutral endopeptidase, is gaining attention for its role in tumor growth regulation. Neprilysin expressions are positively correlated with several tumors including GBM and reduced expression of NEP protein is associated with the pathogenesis of multiple tumors. One of the main reasons for NEP protein downregulation is the action of Histone deacetylase (HDAC) enzymes, especially HDAC1. Additionally, studies have reported that increased levels of HDAC1 are responsible for downregulating NEP gene expression. Hence, HDAC1 inhibition can be a good target to elevate NEP levels, which can be a good therapeutic approach to GBM. This study utilizes the computational drug repurposing tool, Schrodinger Maestro to identify HDAC1 inhibitors from the ZINC15 database.1379 FDA-approved drugs from the ZINC15 database were screened through molecular docking. Based on docking score and ligand-protein interaction, the top ten molecules were selected which were then subjected to binding energy calculation and molecular dynamics (MD) simulations. The three most active drugs from the MD simulations- ZINC22010649 (Panobinostat), ZINC4392649 (Tasimelteon) and ZINC1673 (Melphalan), were tested on C6 and U87 MG glioblastoma cells for cytotoxicity and HDAC1 protein levels using western blot analysis. Among the three drugs, Panobinostat exhibited potent cytotoxic action and showed a significant reduction in the HDAC1 protein levels.Communicated by Ramaswamy H. Sarma.