Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease and its incidence rate is rapidly rising.However,effective therapies for the treatment of IPF are still lacking.Phosphodiesterase 4(PDE4)inhibitors were ...Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease and its incidence rate is rapidly rising.However,effective therapies for the treatment of IPF are still lacking.Phosphodiesterase 4(PDE4)inhibitors were reported to be potential anti-fibrotic agents.Herein,structure-based hit-to-lead optimization of natural isoaurostatin(8.98μmol/L)resulted in several potent inhibitors of PDE4 with half maximal inhibitory concentration(IC_(50))values ranging from 35 nmol/L to 126 nmol/L.Co-crystal structures revealed that isoaurostatin compounds exhibited different binding patterns from the classic PDE4 inhibitor rolipram and the analogues would favor to be Z configurations other than the corresponding E isomers.Finally,lead 2–9 showed remarkable in vitro/in vivo anti-fibrotic effects indicating its potential as a novel anti-IPF agent.展开更多
磷酸二酯酶7和4(phosphodiesterase 7 and 4,PDE7 and PDE4)作为特异性水解第二信使3',5'-环腺苷酸的蛋白酶,是治疗炎症等相关疾病的重要靶点。本文以37个噻吩并嘧啶酮类PDE7和PDE4双重抑制剂为研究对象,采用比较分子相似性指...磷酸二酯酶7和4(phosphodiesterase 7 and 4,PDE7 and PDE4)作为特异性水解第二信使3',5'-环腺苷酸的蛋白酶,是治疗炎症等相关疾病的重要靶点。本文以37个噻吩并嘧啶酮类PDE7和PDE4双重抑制剂为研究对象,采用比较分子相似性指数分析(Co MSIA),研究其影响化合物抑制活性的特征结构信息。结果表明,这两类抑制剂的Co MSIA的预测能力较强(Rpre2≥0.80)。其影响分子生物活性的共同特征结构主要是:(1)噻吩环上的R_2取代基为疏水场的敏感区域;(2)嘧啶酮环和R_3取代基的链接基益于采用含氢键供体的亲水性基团;(3)噻吩环所在区域益于引入包含氢键供体的基团。研究还发现,PDE7抑制剂的R_1和R_2取代基,分别适宜结合小体积的亲水性基团和大体积的基团。PDE4抑制剂的嘧啶酮环和R3取代基的链接基益于结合正电基团。本研究所得的模型和信息,可为后续新型抑制剂的设计开发提供理论指导。展开更多
基金supported by the Natural Science Foundation of China(Nos.22277019,82150204,22307031,22377023,22077143,and 82003594)Key Project of Guangdong Natural Science Foundation(No.2016A030311033)+2 种基金Fundamental Research Funds for Hainan University(Nos.KYQD(ZR)-21031,KYQD(ZR)-21108,KYQD(ZR)-23003,and XTCX2022JKA01)Guangdong Provincial Key Laboratory of Construction Foundation(No.2023B1212060022)Science Foundation of Hainan Province(Nos.KJRC2023B10,824YXQN420,and 324MS018)。
文摘Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease and its incidence rate is rapidly rising.However,effective therapies for the treatment of IPF are still lacking.Phosphodiesterase 4(PDE4)inhibitors were reported to be potential anti-fibrotic agents.Herein,structure-based hit-to-lead optimization of natural isoaurostatin(8.98μmol/L)resulted in several potent inhibitors of PDE4 with half maximal inhibitory concentration(IC_(50))values ranging from 35 nmol/L to 126 nmol/L.Co-crystal structures revealed that isoaurostatin compounds exhibited different binding patterns from the classic PDE4 inhibitor rolipram and the analogues would favor to be Z configurations other than the corresponding E isomers.Finally,lead 2–9 showed remarkable in vitro/in vivo anti-fibrotic effects indicating its potential as a novel anti-IPF agent.
文摘磷酸二酯酶7和4(phosphodiesterase 7 and 4,PDE7 and PDE4)作为特异性水解第二信使3',5'-环腺苷酸的蛋白酶,是治疗炎症等相关疾病的重要靶点。本文以37个噻吩并嘧啶酮类PDE7和PDE4双重抑制剂为研究对象,采用比较分子相似性指数分析(Co MSIA),研究其影响化合物抑制活性的特征结构信息。结果表明,这两类抑制剂的Co MSIA的预测能力较强(Rpre2≥0.80)。其影响分子生物活性的共同特征结构主要是:(1)噻吩环上的R_2取代基为疏水场的敏感区域;(2)嘧啶酮环和R_3取代基的链接基益于采用含氢键供体的亲水性基团;(3)噻吩环所在区域益于引入包含氢键供体的基团。研究还发现,PDE7抑制剂的R_1和R_2取代基,分别适宜结合小体积的亲水性基团和大体积的基团。PDE4抑制剂的嘧啶酮环和R3取代基的链接基益于结合正电基团。本研究所得的模型和信息,可为后续新型抑制剂的设计开发提供理论指导。
