Department of Pharmacology, PGIMER, Chandigarh, India.
PLoS One. 2022 Jul 25;17(7):e0268139. doi: 10.1371/journal.pone.0268139. eCollection 2022.
Metal-dependent histone deacetylases (HDACs) are essential epigenetic regulators; their molecular and pharmacological roles in medically critical diseases such as neuropsychiatric disorders, neurodegeneration, and cancer are being studied globally. HDAC2's differential expression in the central nervous system makes it an appealing therapeutic target for chronic neurological diseases like autism spectrum disorder. In this study, we identified H3R inhibitor molecules that are computationally effective at binding to the HDAC2 metal-coordinated binding site. The study highlights the importance of pitolisant in screening the potential H3R inhibitors by using a hybrid workflow of ligand and receptor-based drug discovery. The screened lead compounds with PubChem SIDs 103179850, 103185945, and 103362074 show viable binding with HDAC2 in silico. The importance of ligand contacts with the Zn2+ ion in the HDAC2 catalytic site is also discussed and investigated for a significant role in enzyme inhibition. The proposed H3R inhibitors 103179850, 103185945, and 103362074 are estimated as dual-active molecules to block the HDAC2-mediated deacetylation of the EAAT2 gene (SLC1A2) and H3R-mediated synaptic transmission irregularity and are, therefore, open for experimental validation.
金属依赖性组蛋白去乙酰化酶（HDACs）是重要的表观遗传调节剂；它们在神经精神疾病、神经退行性疾病和癌症等医学关键疾病中的分子和药理学作用正在全球范围内得到研究。HDAC2 在中枢神经系统中的差异表达使其成为自闭症谱系障碍等慢性神经疾病有吸引力的治疗靶点。在这项研究中，我们鉴定了与 HDAC2 金属配位结合位点具有计算上有效结合的 H3R 抑制剂分子。该研究强调了在使用基于配体和受体的药物发现的混合工作流程筛选潜在 H3R 抑制剂时，匹哚沙明的重要性。筛选出的具有 PubChem SIDs 103179850、103185945 和 103362074 的先导化合物在计算机上显示与 HDAC2 具有可行的结合。还讨论并研究了配体与 HDAC2 催化位点中 Zn2+ 离子的接触在酶抑制中的重要作用。所提出的 H3R 抑制剂 103179850、103185945 和 103362074 被估计为双重活性分子，可阻断 HDAC2 介导的 EAAT2 基因（SLC1A2）去乙酰化和 H3R 介导的突触传递异常，因此可用于实验验证。
