<br>使用复制品交换和溶质回火 (REST) 分子动力学 (MD) 模拟阐明 TH301 对 CRY1 W399 扭转角的影响,Physical Chemistry Chemical Physics

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使用复制品交换和溶质回火 (REST) 分子动力学 (MD) 模拟阐明 TH301 对 CRY1 W399 扭转角的影响
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2023-11-21 , DOI: 10.1039/d3cp04092e
Yeongrae Cho _{1,

2} , Kexin Li _{1,

2} , Jin Hyup Lee _{2,

3} , Seung Pil Pack _{1,

2} , Art E Cho _{1,

2}

Affiliation

隐花色素 1 (CRY1) 是一种参与生物钟并与多种疾病相关的蛋白质。以 CRY1 为靶点进行药物开发需要发现通过泛素化靶向其 FAD 结合位点的竞争性抑制剂。在开发调节 CRY1 的化合物期间，发现了一种名为 TH301 的有趣化合物。尽管与 CRY1 结合，TH301 不会引起预期的反应，被认为是一种无活性的化合物。然而，据观察，TH301 影响 CRY1 的 W399 残基的扭转角，通过影响盖环的运动，在泛素化调节中发挥至关重要的作用。在我们的研究中，我们旨在通过执行基于 REST 的 MD 模拟来了解 TH301 如何导致 CRY1 的 W399 扭转角转变为“异常”。 TH301 的环戊烷倾向于与 W292 平行排列，当 W399 处于“正常状态”时会产生排斥力，导致翻转。在“out-form”中，W399的侧链通过π-π相互作用与TH301的氯苯相互作用，稳定了这一姿势。该分析有助于识别与 CRY1 结合的化合物并过滤掉非活性化合物。我们发现评估 TH301 和 W399 之间的相互作用能对于评估 W399 是否翻转至关重要。这些发现有助于开发针对 CRY1 的药物，并增强我们对其调控机制的理解。

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Elucidating TH301's influence on the torsion angle of CRY1 W399 using replica exchange with solute tempering (REST) molecular dynamics (MD) simulations

Cryptochrome 1 (CRY1) is a protein involved in the circadian clock and associated with various diseases. Targeting CRY1 for drug development requires the discovery of competitive inhibitors that target its FAD binding site through ubiquitination. During the development of compounds to regulate CRY1, an intriguing compound called TH301 was identified. Despite binding to CRY1, TH301 does not induce the expected reaction and is considered an inactive compound. However, it has been observed that TH301 affects the torsion angle of CRY1's W399 residue, which plays a crucial role in the regulation of ubiquitination by influencing the movement of the lid loop. In our research, we aimed to understand how TH301 induces the torsion angle of CRY1's W399 to shift to an “out-form” by performing REST-based MD simulations. The cyclopentane of TH301 tends to align parallel with W292, creating a repulsive force when W399 is in the “in-form”, leading to a flip. In the “out-form”, W399's side chain interacts with TH301's chlorobenzene through a π–π interaction, stabilizing this pose. This analysis helps identify compounds binding to CRY1 and filter out inactive ones. We found that assessing the interaction energy between TH301 and W399 is crucial to evaluate whether W399 flips or not. These findings contribute to the development of drugs targeting CRY1 and enhance our understanding of its regulatory mechanisms.

更新日期：2023-11-21

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