Medicinal Chemistry Research Laboratory, Department of Pharmacy, Guru Ghasidas University, Bilaspur, Chhattisgarh, India.
Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.
J Biomol Struct Dyn. 2024 Jan-Feb;42(1):362-383. doi: 10.1080/07391102.2023.2192804. Epub 2023 Mar 30.
Histone deacetylases (HDACs) are critical epigenetic drug targets that have gained significant attention in the scientific community for the treatment of cancer. The currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Here, we describe our protocol for the discovery of novel potential hydroxamic acid based HDAC3 inhibitors through pharmacophore modeling, virtual screening, docking, molecular dynamics (MD) simulation and toxicity studies. The ten pharmacophore hypotheses were established, and their reliability was validated by different ROC (receiving operator curve) analysis. Among them, the best model (Hypothesis 9 or RRRA) was employed for searching SCHEMBL, ZINC and MolPort database to screen out hit molecules as selective HDAC3 inhibitors, followed by different docking stages. MD simulation (50 ns) and MMGBSA study were performed to study the stability of ligand binding modes and with the help of trajectory analysis, to calculate the ligand-receptor complex RMSD (root-mean-square deviation), RMSF (root-mean-square fluctuation) and H-bond distance, etc. Finally, toxicity studies were performed on top screened molecules and compared with reference drug SAHA and established structure-activity relationship (SAR). The results indicated that compound with high inhibitory potency and less toxicity (probability value 0.418), is suitable for further experimental analysis.Communicated by Ramaswamy H. Sarma.
组蛋白去乙酰化酶（HDACs）是关键的表观遗传药物靶点，在癌症治疗方面受到科学界的广泛关注。目前上市的 HDAC 抑制剂缺乏对各种 HDAC 同工酶的选择性。在这里，我们描述了通过药效团建模、虚拟筛选、对接、分子动力学（MD）模拟和毒性研究来发现新型潜在的基于羟肟酸的 HDAC3 抑制剂的方案。建立了十个药效团假设，并通过不同的 ROC（接收者操作曲线）分析验证了它们的可靠性。其中，最佳模型（假设 9 或 RRRA）用于搜索 SCHEMBL、ZINC 和 MolPort 数据库，以筛选出作为选择性 HDAC3 抑制剂的命中分子，然后进行不同的对接阶段。进行 MD 模拟（50ns）和 MMGBSA 研究以研究配体结合模式的稳定性，并借助轨迹分析计算配体-受体复合物 RMSD（均方根偏差）、RMSF（均方根波动）和氢键距离等。最后，对筛选出的顶级分子进行毒性研究，并与参考药物 SAHA 进行比较，建立结构-活性关系（SAR）。结果表明，具有高抑制活性和低毒性的化合物（概率值为 0.418）适合进一步的实验分析。由 Ramaswamy H. Sarma 交流。
