DataSheet1_Integrated bioinformatics and interaction analysis to advance chronotherapies for mental disorders.pdf

IntroductionRobust connections have been identified between the pathophysiology of mental disorders and the functioning of the circadian system. The overarching objective of this study was to investigate the potential for circadian rhythms to be leveraged for therapeutics in mental disorders.
MethodsWe considered two approaches to chronotherapy–optimal timing of existing medications (“clocking the drugs”) and redressing circadian abnormalities with small molecules (“drugging the clock”). We assessed whether circadian rhythm-modulating compounds can interact with the prominent drug targets of mental disorders utilizing computational tools like molecular docking and molecular dynamics simulation analysis.
ResultsFirstly, an analysis of transcript-level rhythmic patterns in recognized drug targets for mental disorders found that 24-hour rhythmic patterns were measurable in 54.4% of targets in mice and 35.2% in humans. We also identified several drug receptors exhibiting 24-hour rhythmicity involved in critical physiological pathways for neural signaling and communication, such as neuroactive ligand-receptor interaction, calcium signaling pathway, cAMP signaling pathway, and dopaminergic and cholinergic synapses. These findings advocate that further research into the timing of drug administration in mental disorders is urgently required. We observed that many pharmacological modulators of mammalian circadian rhythms, including KL001, SR8278, SR9009, Nobiletin, and MLN4924, exhibit stable binding with psychotropic drug targets.
DiscussionThese findings suggest that circadian clock-modulating pharmacologically active small molecules could be investigated further for repurposing in the treatment of mood disorders. In summary, the present analyses indicate the potential of chronotherapeutic approaches to mental disorder pharmacotherapy and specify the need for future circadian rhythm-oriented clinical research.

研究背景 精神障碍的病理生理学与昼夜节律系统（circadian system）的功能之间已被证实存在稳固的关联。本研究的核心目标在于探究利用昼夜节律为精神障碍患者提供治疗干预的潜在可能性。
研究方法 本研究采用两种时辰疗法（chronotherapy）策略：一是对现有药物进行最优给药时机调控（即“药物时辰调控”），二是通过小分子化合物纠正昼夜节律异常（即“节律靶点药物干预”）。我们借助分子对接、分子动力学模拟分析等计算工具，评估了昼夜节律调节化合物能否与精神障碍的主流药物靶点产生相互作用。
研究结果 首先，对已确认的精神障碍药物靶点的转录水平节律模式进行分析后发现，小鼠体内54.4%的靶点可检测到24小时节律模式，人类体内该比例为35.2%。本研究还鉴定出多种参与神经信号传导与通讯关键生理通路的24小时节律性药物受体，涵盖神经活性配体-受体相互作用、钙信号通路、环腺苷酸（cAMP）信号通路以及多巴胺能、胆碱能突触等通路。上述结果表明，针对精神障碍患者的给药时机相关研究亟待进一步开展。我们还观察到，多种哺乳动物昼夜节律的药理学调节剂（包括KL001、SR8278、SR9009、诺比列亭（Nobiletin）以及MLN4924）均可与精神药物靶点形成稳定结合。
讨论 上述研究结果提示，可进一步探索以昼夜节律为靶点的药理学活性小分子化合物，将其重新定位用于情感障碍（mood disorders）的治疗。综上，本研究分析证实了时辰疗法应用于精神障碍药物治疗的潜力，并明确了未来开展面向昼夜节律的临床研究的必要性。