Design of Potent Panobinostat Histone Deacetylase Inhibitor Derivatives: Molecular Considerations for Enhanced Isozyme Selectivity between HDAC2 and HDAC8
Design of Potent Panobinostat Histone Deacetylase Inhibitor Derivatives: Molecular Considerations for Enhanced Isozyme Selectivity between HDAC2 and HDAC8
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DOI：
10.1002/minf.201800080
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发表时间：
2019-03-01
影响因子：
3.6
通讯作者：
Watkins, Davita L.
中科院分区：
文献类型：
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作者：
Stoddard, Shana V.;May, Xavier A.;Watkins, Davita L.
组蛋白脱乙酰酶 (HDAC) 是一个由 18 种同工酶组成的重要家族，目前正将其作为多种疾病的药物靶标。 HDAC2 和 HDAC8 是其中两种同工酶，已被确定为抗癌、神经退行性、免疫和抗寄生虫药物设计的药物靶点。有效的 HDAC2 和 HDAC8 抑制剂的设计将有助于许多疾病的治疗进展。这项工作的目的是开发有效的 HDAC2 和 HDAC8 抑制剂。进行了对接研究，比较了 HDAC2 和 HDAC8 中的帕比司他衍生物。我们的六种衍生物显示出比帕比司他更强的与 HDAC2 的结合，我们的两种衍生物显示出比帕比司他更强的与 HDAC8 的结合。我们评估了分子特征，这些特征提高了我们的抑制剂相对于帕比司他的效力，并且还确定了另一种分子考虑因素，可用于增强组蛋白脱乙酰酶抑制剂 (HDACi) 对 HDAC2 或 HDAC8 同工酶的选择性。这项工作的结果可用于协助未来为 HDAC2 和 HDAC8 设计更有效、更具选择性的 HDACi。
Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti-cancer, neurodegenerative, immunological, and anti-parasitic agents. Design of potent HDAC2 and HDAC8 inhibitors will be useful for the therapeutic advances in many disorders. This work was undertaken to develop potent HDAC2 and HDAC8 inhibitors. A docking study was performed comparing panobinostat derivatives in both HDAC2 and HDAC8. Six of our derivatives showed stronger binding to HDAC2 than panobinostat, and two of our derivatives showed stronger binding to HDAC8 than panobinostat. We evaluated the molecular features, which improved potency of our inhibitors over panobinostat and also identified another molecular consideration, which could be used to enhance histone deacetylase inhibitor (HDACi) selectivity towards either the HDAC2 or HDAC8 isozymes. The results of this work can be used to assist future design of more potent and selective HDACi for HDAC2 and HDAC8.