Department of Chemistry, National Institute of Technology Durgapur, Durgapur, India.
Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, India.
J Biomol Struct Dyn. 2024 Apr;42(7):3535-3562. doi: 10.1080/07391102.2023.2213346. Epub 2023 May 22.
Herein, we report a blended ligand and structure-based pharmacophore screening approach to identify new natural leads against the Protein Lysine Methyltransferase 2 (EHMT2/G9a). The EHMT2/G9a has been associated with Cancer, Alzheimer's, and aging and is considered an emerging drug target having no clinically passed inhibitor. Purposefully, we developed the ligand-based pharmacophore (Pharmacophore-L) based on the common features of known inhibitors and the structure-based pharmacophore (Pharmacophore-S) based on the interaction profile of available crystal structures. The Pharmacophore-L and Pharmacophore-S were subjected to multiple tiers of validations and utilized in combination for the screening of total 741543 compounds coming from multiple databases. Additional layers of stringency were applied in the screening process to test drug-likeness (using Lipinski's rule, Veber's rule, SMARTS and ADMET filtration), to rule out any toxicity (TOPKAT analysis). The interaction profiles, stabilities, and comparative analysis against the reference were carried out by flexible docking, MD simulation, and MM-GBSA analysis, which finally led to three leads as potential inhibitors of G9a.Communicated by Ramaswamy H. Sarma.
在这里，我们报告了一种混合配体和基于结构的药效团筛选方法，用于鉴定针对蛋白赖氨酸甲基转移酶 2（EHMT2/G9a）的新型天然先导化合物。EHMT2/G9a 与癌症、阿尔茨海默病和衰老有关，被认为是一个新兴的药物靶点，目前没有经过临床验证的抑制剂。有针对性地，我们基于已知抑制剂的共同特征开发了基于配体的药效团（药效团-L），并基于现有晶体结构的相互作用模式开发了基于结构的药效团（药效团-S）。药效团-L 和药效团-S 经过多轮验证，并结合使用，对来自多个数据库的总计 741543 种化合物进行了筛选。在筛选过程中应用了额外的严格性层，以测试药物相似性（使用 Lipinski 规则、Veber 规则、SMARTS 和 ADMET 过滤），排除任何毒性（TOPKAT 分析）。通过柔性对接、MD 模拟和 MM-GBSA 分析进行了相互作用模式、稳定性和与参比物的比较分析，最终得出了三个作为 G9a 潜在抑制剂的先导化合物。由 Ramaswamy H. Sarma 传达。
