AIM: Inhibitors of catechol-O-methyltransferase (COMT) have always been administered to improve the bioavailability of L-Dopa in the treatment of Parkinson disease (PD). A new three-dimensional quantitative structure-...AIM: Inhibitors of catechol-O-methyltransferase (COMT) have always been administered to improve the bioavailability of L-Dopa in the treatment of Parkinson disease (PD). A new three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis is performed to correlate the molecular fields with percent inhibition values. METHODS: Three predictive models were derived based on 36 previously reported COMT inhibitors employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methodologies. RESULTS: The CoMFA model and CoMSIA model with steric and electrostatic field yielded cross-validated rcv2 0.585 and 0.528 respectively, whereas the conventional rncv2 were 0.979 and 0.891. The CoMSIA model with hydrophobic field exhibited rcv2 0.544 and rncv2 0.930. CONCLUSION: The derived models from CoMFA and CoMSIA all exhibit good prediction for both internal and external validations. The individual inspection of 3D contours generated from these models helps in understanding the possible region for structural modification of molecules to improve the inhibitory bioactivity. The 3D-QSAR models may be useful in designing and predicting novel COMT inhibitors.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
The quantitative structure-activity relationship(QSAR) of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives was studied.Three different alignment methods were used to get the models of the comparative molecular field...The quantitative structure-activity relationship(QSAR) of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives was studied.Three different alignment methods were used to get the models of the comparative molecular field analysis(CoMFA),the comparative molecular similarity indices analysis(CoMSIA),and the hologram quantitative structure?activity relationship(HQSAR).The statistical results from the established models show believable predictivity based on the cross-validated value(q2>0.5) and the non-validated value(r2>0.9),The analysis on contour maps of CoMFA and CoMSIA models suggests that hydrophobic and hydrogen-bond acceptor fields are important factors that affect the AT1 antagonistic activity of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives besides the steric and electrostatic fields,The structural modification information from different atom contributions in the HQSAR model is in agreement with that in the 3D-QSAR models.展开更多
文摘AIM: Inhibitors of catechol-O-methyltransferase (COMT) have always been administered to improve the bioavailability of L-Dopa in the treatment of Parkinson disease (PD). A new three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis is performed to correlate the molecular fields with percent inhibition values. METHODS: Three predictive models were derived based on 36 previously reported COMT inhibitors employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methodologies. RESULTS: The CoMFA model and CoMSIA model with steric and electrostatic field yielded cross-validated rcv2 0.585 and 0.528 respectively, whereas the conventional rncv2 were 0.979 and 0.891. The CoMSIA model with hydrophobic field exhibited rcv2 0.544 and rncv2 0.930. CONCLUSION: The derived models from CoMFA and CoMSIA all exhibit good prediction for both internal and external validations. The individual inspection of 3D contours generated from these models helps in understanding the possible region for structural modification of molecules to improve the inhibitory bioactivity. The 3D-QSAR models may be useful in designing and predicting novel COMT inhibitors.
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。
基金Project(20876180) supported by the National Natural Science Foundation of China
文摘The quantitative structure-activity relationship(QSAR) of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives was studied.Three different alignment methods were used to get the models of the comparative molecular field analysis(CoMFA),the comparative molecular similarity indices analysis(CoMSIA),and the hologram quantitative structure?activity relationship(HQSAR).The statistical results from the established models show believable predictivity based on the cross-validated value(q2>0.5) and the non-validated value(r2>0.9),The analysis on contour maps of CoMFA and CoMSIA models suggests that hydrophobic and hydrogen-bond acceptor fields are important factors that affect the AT1 antagonistic activity of 2-alkyl-4-(biphenylylmethoxy) pyridine derivatives besides the steric and electrostatic fields,The structural modification information from different atom contributions in the HQSAR model is in agreement with that in the 3D-QSAR models.
