PDF(Pubmed)
Abstract：
REV-ERBα, a therapeutically promising nuclear hormone receptor, plays a crucial role in regulating various physiological processes such as the circadian clock, inflammation, and metabolism. However, the availability of chemical probes to investigate the pharmacology of this receptor is limited, with SR8278 being the only identified synthetic antagonist. Moreover, no X-ray crystal structures are currently available that demonstrate the binding of REV-ERBα to antagonist ligands. This lack of structural information impedes the development of targeted therapeutics. To address this issue, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to investigate the binding pathway of SR8278 to REV-ERBα. For comparison, we also used GaMD to observe the ligand binding process of STL1267, for which an X-ray structure is available. GaMD simulations successfully captured the binding of both ligands to the receptor\'s orthosteric site and predicted the ligand binding pathway and important amino acid residues involved in the antagonist SR8278 binding. This study highlights the effectiveness of GaMD in investigating protein-ligand interactions, particularly in the context of drug recognition for nuclear hormone receptors.
摘要：
REV-ERBα,一种有治疗前景的核激素受体，在调节各种生理过程中起着至关重要的作用，如生物钟，炎症,和新陈代谢。然而,研究这种受体药理学的化学探针的可用性是有限的，SR8278是唯一确定的合成拮抗剂。此外，目前没有X-射线晶体结构证明REV-ERBα与拮抗剂配体的结合。这种结构信息的缺乏阻碍了靶向疗法的发展。为了解决这个问题，我们采用高斯加速分子动力学（GaMD）模拟来研究SR8278与REV-ERBα的结合途径。为了比较，我们还使用GaMD观察了STL1267的配体结合过程，对此有X射线结构。GaMD模拟成功捕获了两种配体与受体正构位点的结合，并预测了配体结合途径和参与拮抗剂SR8278结合的重要氨基酸残基。这项研究强调了GaMD在研究蛋白质-配体相互作用中的有效性，特别是在核激素受体的药物识别方面。
