新型二羟酸酯衍生物对组蛋白去乙酰化酶的抑制作用

Jhawn G Saul, Andrew E Huckleby, Maia C Gugello, Jonathan Urbanczyk, Staci Desmarais, Hyunshun Shin, Apparao Bokka, Junha Jeon, Jatindra N Tripathy, Sung-Kun Kim
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引用次数: 0

摘要

背景:组蛋白去乙酰化酶1 (HDAC1)是一种重要的表观遗传调控因子,参与染色质重塑和转录抑制,使其成为癌症治疗的重要靶点。选择性抑制HDAC1是一种很有前途的癌症治疗方法,因为它可以调节基因表达并诱导肿瘤细胞凋亡。方法:设计了两种新型羟酸盐基HDAC1抑制剂化合物4和6,并通过分子对接、分子动力学(MD)模拟和酶抑制实验对其进行了评价。分子对接评估了结合相互作用,而MD模拟评估了配体-蛋白质复合物的稳定性。酶抑制法测定IC50值并评价化合物的效价。结果:分子对接显示,这两种化合物都与HDAC1表现出显著的相互作用,包括疏水接触、氢键和锌配位。化合物4的结合亲和力(-6.2 kcal/mol)高于化合物6 (-5.7 kcal/mol)。MD模拟证实,化合物4具有较高的稳定性,具有二价锌配位(4.3 Å和4.8 Å),而化合物6具有较弱的一价锌配位(4.4 Å)。酶测结果表明,化合物4的IC50为2.96±0.4 μM,化合物6的IC50为4.76±0.5 μM;因此,化合物4具有较好的抑制效力。结论:与化合物6相比,化合物4具有更强的结合亲和力、稳定性和酶抑制作用,这表明该化合物可能成为开发选择性HDAC1抑制剂的有希望的先导物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibitory Effect of Novel Dihydroxamate Derivatives for Histone Deacetylase 1.

Background: Histone deacetylase 1 (HDAC1) is a critical epigenetic regulator involved in chromatin remodeling and transcriptional repression, making it a valuable target for cancer therapy. Selective inhibition of HDAC1 represents a promising approach to cancer treatment, as it modulates gene expression and induces apoptosis in tumor cells.

Methods: Two novel hydroxamate-based HDAC1 inhibitors, compounds 4 and 6, were designed and evaluated using molecular docking, molecular dynamics (MD) simulations, and enzymatic inhibition assays. Molecular docking assessed binding interactions, while MD simulations evaluated the stability of the ligand-protein complexes. Enzymatic inhibition assays were used to determine the IC50 values and evaluate the potency of the compounds.

Results: Molecular docking revealed that both compounds exhibited significant interactions with HDAC1, including hydrophobic contacts, hydrogen bonding, and zinc coordination. Compound 4 demonstrated a stronger binding affinity (-6.2 kcal/mol) compared to compound 6 (-5.7 kcal/mol). The MD simulations confirmed that compound 4 exhibited greater stability, with divalent zinc coordination (4.3 Å and 4.8 Å), whereas compound 6 showed weaker monovalent coordination (4.4 Å). Enzymatic assays demonstrated that compound 4 had an IC50 of 2.96 ± 0.4 μM, while compound 6 exhibited an IC50 of 4.76 ± 0.5 μM; thus, compound 4 possesses superior inhibitory potency.

Conclusions: Compound 4 exhibits enhanced binding affinity, stability, and enzymatic inhibition compared to compound 6, suggesting that this compound may serve as a promising lead for the development of selective HDAC1 inhibitors.

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