School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
Molecules. 2023 Jul 10;28(14):5315. doi: 10.3390/molecules28145315.
As one of the crucial targets of epigenetics, histone lysine-specific demethylase 1 (LSD1) is significant in the occurrence and development of various tumors. Although several irreversible covalent LSD1 inhibitors have entered clinical trials, the large size and polarity of the FAD-binding pocket and undesired toxicity have focused interest on developing reversible LSD1 inhibitors. In this study, targeting the substrate-binding pocket of LSD1, structure-based and ligand-based virtual screenings were adopted to expand the potential novel structures with molecular docking and pharmacophore model strategies, respectively. Through drug-likeness evaluation, ADMET screening, molecular dynamics simulations, and binding free energy screening, we screened out one and four hit compounds from the databases of 2,029,554 compounds, respectively. Generally, these hit compounds can be divided into two categories, amide ( and ) and 1,2,4-triazolo-4,3-α-quinazoline (). Among them, exhibits the strongest binding affinity. Finally, the binding mechanisms of the hit compounds were further calculated in detail by the residue free energy decomposition. It was found that van der Waals interactions contribute most to the binding, and is also helpful in stabilizing the binding and avoiding off-target effects. We believe this work not only provides a solid theoretical foundation for the design of LSD1 substrate reversible inhibitors, but also expands the diversity of parent nucleus, offering new insights for synthetic chemists.
作为表观遗传学的关键靶点之一，组蛋白赖氨酸特异性去甲基化酶 1（LSD1）在各种肿瘤的发生和发展中具有重要意义。尽管几种不可逆的 LSD1 共价抑制剂已进入临床试验，但 FAD 结合口袋的大尺寸和极性以及不理想的毒性引起了人们对开发可逆 LSD1 抑制剂的兴趣。在这项研究中，针对 LSD1 的底物结合口袋，采用基于结构和基于配体的虚拟筛选方法，分别通过分子对接和药效团模型策略来扩展潜在的新型结构。通过药物相似性评估、ADMET 筛选、分子动力学模拟和结合自由能筛选，我们从包含 2029554 个化合物的数据库中分别筛选出一个和四个命中化合物。一般来说，这些命中化合物可以分为酰胺（和）和 1,2,4-三唑并[4,3-α]喹唑啉（）两类。其中，表现出最强的结合亲和力。最后，通过残基自由能分解进一步详细计算了命中化合物的结合机制。结果发现，范德华相互作用对结合贡献最大，而也有助于稳定结合并避免脱靶效应。我们相信这项工作不仅为 LSD1 底物可逆抑制剂的设计提供了坚实的理论基础，而且还扩展了母体核的多样性，为合成化学家提供了新的见解。
