Nagamani Selvaraman, Muthusamy Karthikeyan, Marshal J John
a Department of Bioinformatics , Alagappa University , Karaikudi 630 004 , India.
J Biomol Struct Dyn. 2016 Oct;34(10):2233-2250. doi: 10.1080/07391102.2015.1111168. Epub 2016 Mar 11.
Chronic kidney disease (CKD) is a prominent health issue reported globally. The level of the vitamin D receptor (VDR) and cytochrome P450 enzyme 24-hydroxylase (CYP24A1) are crucial in the pathogenesis of secondary hyperparathyroidism (sHPT) in CKD. An elevated expression of the CYP24A1 leads to the deficiency of vitamin D and resistance to vitamin D therapy. Hence, VDR agonists and CYP24A1 antagonists are suggested to CKD patients for the management of biochemical complications. CTA-018 is a recently reported analog and acts as a potent CYP24A1 inhibitor. It inhibits CYP24A1 with an IC 27 ± 6 nM, about 10 times more potentially than the non-selective inhibitor ketoconazole (253 ± 20 nM), and it is also been reported to induce the VDR expression. Thus, CTA-018 is under clinical trial among CKD patients. In this study, combined molecular docking and pharmacophore filtering were employed to identify compounds better than CTA-018. A huge set of 9127 compounds from Sweet Lead database were docked into the active site of VDR using Glide XP program. E-pharmacophore was developed from both the targets along with CTA-018. The compounds retrieved from the two different pharmacophore-based screening were re-docked into the active site of CYP24A1. The hits that bind well at both the active sites and matched with the pharmacophore models were considered as possible dual functional molecules against VDR and CYP24A1. Further, molecular dynamics simulation and subsequent energy decomposition analyses were also performed to study the role of specific amino acids in the active site of both VDR and CYP24A1.
慢性肾脏病（CKD）是全球报道的一个突出的健康问题。维生素D受体（VDR）和细胞色素P450酶24-羟化酶（CYP24A1）的水平在CKD继发性甲状旁腺功能亢进（sHPT）的发病机制中至关重要。CYP24A1表达升高会导致维生素D缺乏和对维生素D治疗的抵抗。因此，建议CKD患者使用VDR激动剂和CYP24A1拮抗剂来管理生化并发症。CTA-018是最近报道的一种类似物，是一种有效的CYP24A1抑制剂。它以27±6 nM的IC抑制CYP24A1，其效力约为非选择性抑制剂酮康唑（253±20 nM）的10倍，并且据报道它还能诱导VDR表达。因此，CTA-018正在CKD患者中进行临床试验。在本研究中，采用分子对接和药效团筛选相结合的方法来鉴定比CTA-018更好的化合物。使用Glide XP程序将来自Sweet Lead数据库的9127种化合物对接至VDR的活性位点。从两个靶点以及CTA-018开发了电子药效团。从两种基于不同药效团的筛选中检索到的化合物重新对接至CYP24A1的活性位点。在两个活性位点均结合良好且与药效团模型匹配的命中化合物被视为可能针对VDR和CYP24A1的双功能分子。此外，还进行了分子动力学模拟及随后的能量分解分析，以研究特定氨基酸在VDR和CYP24A1活性位点中的作用。
