Department of Bioinformatics, Alagappa University, Karaikudi, India.
PLoS One. 2018 Oct 4;13(10):e0203194. doi: 10.1371/journal.pone.0203194. eCollection 2018.
The level of the vitamin D in the bloodstream is regulated by cytochrome P450 enzyme 24-hydroxylase A1 (CYP24A1). Over expression of CYP24A1 enzyme is correlated with vitamin D deficiency and resistance to vitamin D therapy. Chronic kidney disease (CKD) patients are commonly reported with the above said expression variations. This deregulation could be solved by ligands that act as a vitamin D receptor (VDR) agonists and CYP24A1 antagonists. Posner et al., (2010) first time reported two new vitamin D analogues namely CTA-091 and CTA-018 to inhibit CYP24A1. The CTA-018 inhibited CYP24A1 with an IC50 27 ± 6 nM (10 times more potent than the ketoconazole (253 ± 20 nM)). CTA-018 induced VDR expression (15-fold lower than 1α,25(OH)2D3) and is under phase II clinical trial, whereas CTA-091 was not able to efficiently induce the VDR expression (>2000 nM). To explore the molecular mechanism, binding specificity of these two vitamin D analogues along with native ligand was extensively studied through in silico approaches. Through molecular dynamics simulations studies, we shown that the sulfonic group (O = S = O) in the side chain of CTA-018 plays an important role in the regulation of VDR agonistic activity. The electron lone pairs of the sulfonic group that interacted with His393 lead to be a factor for agonistic mechanism of VDR activity. Compared to azol-based compounds, CTA-018 binds the different sites in the CYP24A1 binding cavity and thus it could be a potent antagonistic for CYP24A1enzyme.
血液中维生素 D 水平受细胞色素 P450 酶 24-羟化酶 A1（CYP24A1）调节。CYP24A1 酶的过度表达与维生素 D 缺乏和对维生素 D 治疗的抵抗有关。慢性肾脏病（CKD）患者常表现出上述表达变化。这种失调可以通过作为维生素 D 受体（VDR）激动剂和 CYP24A1 拮抗剂的配体来解决。Posner 等人（2010 年）首次报道了两种新型维生素 D 类似物，即 CTA-091 和 CTA-018，以抑制 CYP24A1。CTA-018 抑制 CYP24A1 的 IC50 为 27±6 nM（比酮康唑（253±20 nM）强 10 倍）。CTA-018 诱导 VDR 表达（比 1α,25(OH)2D3 低 15 倍），并正在进行 II 期临床试验，而 CTA-091 不能有效地诱导 VDR 表达（>2000 nM）。为了探索分子机制，通过计算机模拟方法广泛研究了这两种维生素 D 类似物及其天然配体的结合特异性。通过分子动力学模拟研究，我们表明 CTA-018 侧链中的磺酸基（O=S=O）在调节 VDR 激动活性方面起着重要作用。磺酸基的孤对电子与 His393 相互作用，成为 VDR 活性激动机制的一个因素。与唑基化合物相比，CTA-018 结合 CYP24A1 结合腔中的不同位点，因此它可能是 CYP24A1 酶的有效拮抗剂。
