National Supercomputing Center in Zhengzhou, Zhengzhou University, Zhengzhou, Henan 450001, China.
Key Lab of Advanced Drug Preparation Technologies, Ministry of Education of China, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
J Chem Inf Model. 2024 Jun 24;64(12):4773-4780. doi: 10.1021/acs.jcim.4c00398. Epub 2024 Jun 5.
Lysine-specific demethylase 1 (LSD1), a highly sophisticated epigenetic regulator, orchestrates a range of critical cellular processes, holding promising therapeutic potential for treating diverse diseases. However, the clinical research progress targeting LSD1 is very slow. After 20 years of research, only one small-molecule drug, BEA-17, targeting the degradation of LSD1 and CoREST has been approved by the U.S. Food and Drug Administration. The primary reason for this may be the lack of abundant structural data regarding its intricate functions. To gain a deeper understanding of its conformational dynamics and guide the drug design process, we conducted molecular dynamics simulations to explore the conformational states of LSD1 in the apo state and under the influence of cofactors of flavin adenine dinucleotide (FAD) and CoREST. Our results showed that, across all states, the substrate binding pocket exhibited high flexibility, whereas the FAD binding pocket remained more stable. These distinct dynamical properties are essential for LSD1's ability to bind various substrates while maintaining efficient demethylation activity. Both pockets can be enlarged by merging with adjacent pockets, although only the substrate binding pocket can shrink into smaller pockets. These new pocket shapes can inform inhibitor design, particularly for selectively FAD-competitive inhibitors of LSD1, given the presence of numerous FAD-dependent enzymes in the human body. More interestingly, in the absence of FAD binding, the united substrate and FAD binding pocket are partitioned by the conserved residue of Tyr761, offering valuable insights for the design of inhibitors that disrupt the crucial steric role of Tyr761 and the redox role of FAD. Additionally, we identified pockets that positively or negatively correlate with the substrate and FAD binding pockets, which can be exploited for the design of allosteric or concurrent inhibitors. Our results reveal the intricate dynamical properties of LSD1 as well as multiple novel conformational states, which deepen our understanding of its sophisticated functions and aid in the rational design of new inhibitors.
赖氨酸特异性脱甲基酶 1（LSD1）是一种高度复杂的表观遗传调节剂，它协调着一系列关键的细胞过程，在治疗多种疾病方面具有有前景的治疗潜力。然而，针对 LSD1 的临床研究进展非常缓慢。经过 20 年的研究，只有一种针对 LSD1 和 CoREST 降解的小分子药物 BEA-17 被美国食品和药物管理局批准。造成这种情况的主要原因可能是缺乏其复杂功能的丰富结构数据。为了更深入地了解其构象动力学并指导药物设计过程，我们进行了分子动力学模拟，以研究 apo 状态下和黄素腺嘌呤二核苷酸（FAD）和 CoREST 辅因子影响下 LSD1 的构象状态。我们的结果表明，在所有状态下，底物结合口袋都表现出很高的灵活性，而 FAD 结合口袋则保持更稳定。这些不同的动力学特性对于 LSD1 结合各种底物同时保持高效去甲基化活性是必不可少的。两个口袋都可以通过与相邻口袋合并而扩大，尽管只有底物结合口袋可以收缩成更小的口袋。这些新的口袋形状可以为抑制剂的设计提供信息，特别是对于 LSD1 的 FAD 竞争性抑制剂，因为人体内有许多依赖 FAD 的酶。更有趣的是，在没有 FAD 结合的情况下，保守残基 Tyr761 将联合的底物和 FAD 结合口袋分隔开，这为设计破坏 Tyr761 的关键空间位阻作用和 FAD 的氧化还原作用的抑制剂提供了有价值的见解。此外，我们还确定了与底物和 FAD 结合口袋呈正相关或负相关的口袋，可用于设计别构或同时抑制剂。我们的结果揭示了 LSD1 的复杂动力学特性以及多种新的构象状态，加深了我们对其复杂功能的理解，并有助于合理设计新的抑制剂。
