Bromodomain结构域蛋白4(bromodomain-containing protein 4,BRD4)已成为治疗多种疾病药物设计的重要靶标.最近在实验上发现了几种有效的靶向BRD4的抑制剂,但具体的抑制机理尚不清楚.此工作采用分子动力学模拟,动态相关性分析和结合自...Bromodomain结构域蛋白4(bromodomain-containing protein 4,BRD4)已成为治疗多种疾病药物设计的重要靶标.最近在实验上发现了几种有效的靶向BRD4的抑制剂,但具体的抑制机理尚不清楚.此工作采用分子动力学模拟,动态相关性分析和结合自由能计算研究抑制剂8Q9和8QC与BRD4(1)的结合模式.分子动力学分析表明抑制剂结合对BRD4(1)的结构柔性产生重大影响.同时动态相关性分析进一步表明抑制剂结合极大地改变了BRD4(1)的运动模式.结合自由能计算结果表明范德华相互作用是抑制剂与BRD4(1)结合的主要驱动力.采用基于残基的自由能分解方法评估了分离残基对抑制剂结合的贡献,数据表明氢键相互作用和疏水相互作用是影响抑制剂与BRD4(1)结合的关键因素.本研究有望为设计和开发靶向BRD4的抑制剂提供有意义的理论指导.展开更多
Background A bioactive compound from Paecilomyces tenuipes （BCPT） has an inhibitory effect on monoamine oxidase A （MAO-A） and monoamine oxidase B （MAO-B） in vitro and in vivo, which indicates BCPT may be a poten...Background A bioactive compound from Paecilomyces tenuipes （BCPT） has an inhibitory effect on monoamine oxidase A （MAO-A） and monoamine oxidase B （MAO-B） in vitro and in vivo, which indicates BCPT may be a potential antidepressant. In this study we aimed to study the antidepressant effects of BCPT in the chronic unpredictable stress （CUS） model in rats and explore underlying mechanisms in the hypothalamic-pituitary-adrenal （HPA） axis. Methods The antidepressant effects of BCPT were studied in the chronic unpredictable stress model in rats. Animals were housed isolated, except the control group. Rats were exposed daily to different random stressors from day 1 to 21. Awarding response was detected by calculating the 24-hour consumption of sucrose water. Cortisol （CORT） and adrenocorticotropic hormone （ATCH） contents in serum and arginine vasopressin （AVP） contents in the pituitary body were detected by radio immunoassays. Total RNA of hippocampus or hypothalamus was extracted and subjected to reverse transcription-polymerase chain reaction （RT-PCR） for the measurement of corticotrophin releasing hormone （CRH） mRNA or mineralocorticoid receptor （MR） mRNA and glucocorticoid receptor （GR） mRNA levels. Statistical analyses were performed using one way analysis of variance （ANOVA） followed by Student-Newman-Keuls （SNK） test. Results Chronic unpredictable stress resulted in reduction of sensitivity to reward and abnormality in the HPA axis in the animal model. BCPT improved the reward reaction as measured by increasing sucrose consumption, remarkably reduced serum CORT and ACTH levels and the AVP content in the pituitary body in the CUS-treated rats, decreased the expression of CRH mRNA, enhanced the expression of hippocampus MR mRNA, GR mRNA and decreased the ratio of MR/GR. Conclusions BCPT has potentially antidepressant-like activity and normalized the HPA axis hyperactivity in a CUS model of depression in rats. This may be an important mechanism of its antidepressant effect.展开更多
文摘Bromodomain结构域蛋白4(bromodomain-containing protein 4,BRD4)已成为治疗多种疾病药物设计的重要靶标.最近在实验上发现了几种有效的靶向BRD4的抑制剂,但具体的抑制机理尚不清楚.此工作采用分子动力学模拟,动态相关性分析和结合自由能计算研究抑制剂8Q9和8QC与BRD4(1)的结合模式.分子动力学分析表明抑制剂结合对BRD4(1)的结构柔性产生重大影响.同时动态相关性分析进一步表明抑制剂结合极大地改变了BRD4(1)的运动模式.结合自由能计算结果表明范德华相互作用是抑制剂与BRD4(1)结合的主要驱动力.采用基于残基的自由能分解方法评估了分离残基对抑制剂结合的贡献,数据表明氢键相互作用和疏水相互作用是影响抑制剂与BRD4(1)结合的关键因素.本研究有望为设计和开发靶向BRD4的抑制剂提供有意义的理论指导.
基金the grants from the Anhui Education Department(No.2004KJ194ZD)the Anhui Science & Technology Department (No.04023048)
文摘Background A bioactive compound from Paecilomyces tenuipes （BCPT） has an inhibitory effect on monoamine oxidase A （MAO-A） and monoamine oxidase B （MAO-B） in vitro and in vivo, which indicates BCPT may be a potential antidepressant. In this study we aimed to study the antidepressant effects of BCPT in the chronic unpredictable stress （CUS） model in rats and explore underlying mechanisms in the hypothalamic-pituitary-adrenal （HPA） axis. Methods The antidepressant effects of BCPT were studied in the chronic unpredictable stress model in rats. Animals were housed isolated, except the control group. Rats were exposed daily to different random stressors from day 1 to 21. Awarding response was detected by calculating the 24-hour consumption of sucrose water. Cortisol （CORT） and adrenocorticotropic hormone （ATCH） contents in serum and arginine vasopressin （AVP） contents in the pituitary body were detected by radio immunoassays. Total RNA of hippocampus or hypothalamus was extracted and subjected to reverse transcription-polymerase chain reaction （RT-PCR） for the measurement of corticotrophin releasing hormone （CRH） mRNA or mineralocorticoid receptor （MR） mRNA and glucocorticoid receptor （GR） mRNA levels. Statistical analyses were performed using one way analysis of variance （ANOVA） followed by Student-Newman-Keuls （SNK） test. Results Chronic unpredictable stress resulted in reduction of sensitivity to reward and abnormality in the HPA axis in the animal model. BCPT improved the reward reaction as measured by increasing sucrose consumption, remarkably reduced serum CORT and ACTH levels and the AVP content in the pituitary body in the CUS-treated rats, decreased the expression of CRH mRNA, enhanced the expression of hippocampus MR mRNA, GR mRNA and decreased the ratio of MR/GR. Conclusions BCPT has potentially antidepressant-like activity and normalized the HPA axis hyperactivity in a CUS model of depression in rats. This may be an important mechanism of its antidepressant effect.
