Binding profiles of cholesterol ester transfer protein with current inhibitors: a look at mechanism and drawback
Binding profiles of cholesterol ester transfer protein with current inhibitors: a look at mechanism and drawback
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胆固醇酯转移蛋白与现有抑制剂的结合概况：机制和缺点
DOI：
10.1080/07391102.2017.1363661
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发表时间：
2017
影响因子：
4.4
通讯作者：
Zhang Shengli
中科院分区：
文献类型：
--
作者：
Yang Zhiwei;Cao Yang;Hao Dongxiao;Yuan Xiaohui;Zhang Lei;Zhang Shengli
尽管胆固醇酯转运蛋白（CETP）的药理抑制已被提出作为预防和治疗心血管疾病（CVD）的一种方法，但现有抑制剂的不良反应使人们对抑制剂与CETP的相互作用机制产生了疑问。为此，我们利用分子动力学模拟研究了它们之间的相互作用，并揭示了 CETP 的脂质交换机制。结果表明，torcetrapib、anacetrapib和evacetrapib可以诱导CETP的刚性增加，但降低了Helix X的稳定性和CETP的疏水通道，具有良好的结合能力（ΔGbind，-61.08、-64.23和-61.57 kcal mol−1）。在它们的结合过程中，范德华成分（ΔEvdw + ΔGSA）起主导作用，其抑制作用与残基Cys13、Val198、Gln199、Ser230、His232和Phe263密切相关，可降低N端和C端以及Helix X的柔性以及疏水通道的稳定性，三种抑制剂可以进入疏水通道并促进分子内形成H 键，例如 Thr138–Asn192 和 Arg37–Glu186。此外，这三种抑制剂可以抑制 CETP N 末端开口的形成，考虑到其他发现表明 CETP 转移的隧道机制。论文最后解释了抑制剂疗效不足的可能原因，并提出了针对 CVD 治疗的 CETP 远端的合理性。
Although the pharmacological inhibition of cholesterol ester transport protein (CETP) has been proposed as a method of preventing and treating cardiovascular disease (CVD), the adverse effects of current inhibitors have cast doubt on the interaction mechanisms of inhibitors and CETP. In response, a molecular dynamics simulation was used to investigate their interaction and shed light on the lipid exchange mechanism of CETP. Results showed that torcetrapib, anacetrapib, and evacetrapib can induce the incremental rigidity of CETP, yet decrease the stability of Helix X and the hydrophobic tunnel of CETP, with passable binding abilities (ΔGbind, −61.08, −64.23, and −61.57 kcal mol−1). During their binding processes, Van der Waals components (ΔEvdw + ΔGSA) play a dominant role, and the inhibitory effects closely correlated with residues Cys13, Val198, Gln199, Ser230, His232, and Phe263, which could reduce the flexibility of N- and C- termini and Helix X, as well as the stability of hydrophobic tunnel, into which the three inhibitors could enter and promote the formation of intramolecular H-bonds such as Thr138–Asn192 and Arg37–Glu186. Additionally, the three inhibitors could restrain the formation of an opening at the CETP N-terminal, which given the other findings suggests the tunneling mechanism of CETP transfer. The paper closes with an explanation of conceivable causes of the insufficient efficacy of the inhibitors, and puts forward the rationality in targeting the CETP distal end for CVD therapies.