组蛋白去乙酰化酶3（HDAC3）是一种参与基因表达、凋亡和细胞周期进程的表观遗传调节因子，HDAC3的过表达与多种癌症、神经退行性疾病等有关。因此，HDAC3成为新药设计中一个有前途的药物靶点。在本研究中，我们使用了50个基于苯酰胺的HDAC3选择性抑制剂进行了药效团建模，并利用它进行PHASE配体筛选以检索具有类似药效团特征的化合物。选择最佳假设的数据集抑制剂用于构建3D QSAR模型，生成的3D QSAR模型结果表明，其PLS统计学指标良好，回归系数（R2）为0.89，预测系数（Q2）为0.88，Pearson-R因子为0.94，表明其具有优秀的预测能力。从药效团筛选中检索出的化合物进一步对接到HDAC3上以寻找潜在的抑制剂。根据得分函数对10个化合物M1至M10进行了排序，并进行了引导优化。 Prime MM / GBSA，AutoDock结合自由能和ADMET研究被用来选择引导候选化合物。经过引导优化，四个配体分子M1，M2，M3和M4被确定为HDAC3的潜在引导物。前两个潜在引导物M1和M2被用于与HDAC3进行分子动力学模拟以评估其稳定性。通过分子动力学模拟研究，新设计的引导物M11和M12被鉴定为HDAC3的潜在抑制剂。因此，本研究的结果可为发现具有改善选择性和活性的新型HDAC3抑制剂提供见解。Copyright © 2023 Elsevier Ltd. All rights reserved.

Histone deacetylase 3 (HDAC3) is an epigenetic regulator that involves gene expression, apoptosis, and cell cycle progression, and the overexpression of HDAC3 is accountable for several cancers, neurodegeneracy, and many other diseases. Therefore, HDAC3 emerged as a promising drug target for the novel drug design. Here, we carried out the pharmacophore modeling using 50 benzamide-based HDAC3 selective inhibitors and utilized it for PHASE ligand screening to retrieve the hits with similar pharmacophore features. The dataset inhibitors of best hypotheses used to build the 3D QSAR model and the generated 3D QSAR model resulted in good PLS statistics with a regression coefficient (R2) of 0.89, predictive coefficient (Q2) of 0.88, and Pearson-R factor of 0.94 indicating its excellent predictive ability. The hits retrieved from pharmacophore-based virtual screening were subjected to docking against HDAC3 for the identification of potential inhibitors. A total of 10 hitsM1 to M10 were ranked using their scoring functions and further subject to lead optimization. The Prime MM/GBSA, AutoDock binding free energies, and ADMET studies were implemented for the selection of lead candidates. The four ligand molecules M1, M2, M3, and M4 were identified as potential leads against HDAC3 after lead optimization. The top two leads M1 and M2 were subjected to MD simulations for their stability evaluation with HDAC3. The newly designed leads M11 and M12 were identified as HDAC3 potential inhibitors from MD simulations studies. Therefore, the outcomes of the present study could provide insights into the discovery of new potential HDAC3 inhibitors with improved selectivity and activity against a variety of cancers and neurodegenerative diseases.Copyright © 2023 Elsevier Ltd. All rights reserved.