基于量子化学计算的药物活性定量构效关系研究
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摘要
定量构效关系研究(QSAR)是一种借助分子的理化性质参数或结构参数来定量预测其化学特性的方法,通过建立适当的数学模型预测未知化合物的活性,研究药物生理活性和分子结构参数间的量变规律,对探讨药物作用机理,指导新药的设计与合成有重要的意义。
本论文运用偏最小二乘回归、穷举回归和混沌遗传神经网络方法分别对醛糖还原酶抑制剂、趋化因子受体5(CCR5)拮抗剂、6-氟-4-氧-1, 4-二氢喹啉-3-羧基衍生物抗菌活性和环氧合酶-2选择性抑制剂四个体系进行了定量构效关系研究。
糖尿病是一种严重危害人们健康的常见慢性疾病,在导致人类死亡的疾病中居第三位,仅次于心脑血管疾病和肿瘤,其慢性并发症是糖尿病致死致残的主要原因。经研究证明,醛糖还原酶活性增高是导致糖尿病慢性并发症的主要原因之一,因此抑制醛糖还原酶活性成为治疗糖尿病并发症的一种策略。本章就2,4-噻唑烷二酮类化合物作为醛糖还原酶抑制剂进行了QSAR研究,为寻找高活性抗炎药物提供理论指导。
人类获得性免疫缺陷综合症—艾滋病主要是由于人类免疫缺陷病毒1型(HIV-1)病毒感染,在体内快速繁殖并导致宿主白细胞的大量破坏所致。世界各地都在努力防止HIV-1的扩散,但艾滋病毒的感染者人数仍继续上升。CCR5,作为G蛋白偶联因子超家族(GPCR)成员的细胞膜蛋白,是HIV-1入侵机体细胞的主要辅助受体之一,以CCR5为靶点的HIV-1受体拮抗剂越来越受关注。本章对CCR5拮抗剂进行了定量结构活性关系研究,期待为实验工作者合成新药提供理论参考。
结核病是由结核分枝杆菌感染所致,困扰人类已有数千年之久。世界卫生组织统计约1/3的世界人口被结核病感染,全球每年约800万新结核病例和200万死亡患者,并于1993年和2004年两度发布“全球结核紧急状态”预警。本章对51个6-氟-4-氧喹啉-3-羧基衍生物进行了定量结构活性关系研究,以期为设计合成更高抗菌活性的该类药物提供理论参考。
非甾体抗炎药具有抗炎、解热、镇痛等作用,在临床上被广泛用于治疗类风湿性关节炎、骨关节炎等疾病,该类药物通过抑制环氧合酶阻断前列腺素的生物合成而起作用。环氧合酶-2在大多数正常组织中不表达,但在细胞受到各种刺激,如细胞因子、炎症因子、促癌剂等的诱导下会迅速合成,参与炎症过程和肿瘤的发生。因此,对环氧合酶-2的深入研究将为合成新的非甾体抗炎药提供新的靶点。本章建立了1,2-二芳基咪唑类环氧合酶-2选择性抑制剂药物活性与其结构的定量关系模型,根据研究结果讨论了计算的参数对抗菌活性的影响,为寻找高活性抗炎药物提供理论指导。
Quantitative structure-activity relationship (QSAR) is a method of predicting molecular chemistry characteristics from the parameters of physical-chemical and molecular structure. QSAR researches the molecule simulation, which based on quantum chemical computation, were combined to offer a new route to seek several precursor compounds with biologic and medical activity. With quantitative structure-activity relationship analysis, it is possible to analyze the probable structural elements affecting the biological activity of compounds. The information can be used in designing new bioactive compounds and exploring the mechanism of drugs.
In this thesis, the QSAR studies for antimycobacterial activity of aldose reductase inhibitors, chemokine receptor antagonist, 6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid derivatives, selective inhibitor of cyclooxygenase-2 were carried out by using partial least-squares regression, exhaustive linear regression and chaos genetic neural network. According to these models, we discussed the effects of these parameters on inhibitory activity.
Diabetes is a chronic disease which is very harmful to people’s health. It is the third factor leading human to death, inferior to cardiovascular diseases and tumor. Diabetes control and complications is the main reason for diabetes death and disability. The studies have shown that the increased activity of aldose reductase leading to diabetes control and complications, so inhibiting aldose reductase can be a strategy for diabetic complications. We herein describe analysis of 2, 4-thiazolidinediones as inhibitors of aldose reductase.The relevance of the QSAR model obtained for the design of novel derivatives should be assessed not only in terms of predictivity, but also in terms of their ability to provide a chemical and structural explanation of their binding interaction. The results obtained here will be useful for the design of new aldose reductase inhibitors.
The human acquired immunodeficiency syndrome (AIDS) is mainly due to human immunodeficiency virus type 1 (HIV-1) infection, which is rapid propagation of the body and lead to damage huge amount of white blood cells. Despite worldwide efforts to prevent the spread of HIV-1, the number of HIV-1 infected people still continues to rise. CCR5, a membrane protein on cell surface, is a member of G protein-coupled receptor superfamily and one of the major co-receptors for HIV-1 infection was received with excitement in the scientific community as a potential new target for antiviral therapy. In this paper, the quantitative structure-activity relationship studies on CCR5 antagonist, according to the results of QSAR studies, we put forward a number of high activities of CCR5 antagonist in theory, and look forward to experimental confirmation. The QSAR results can offer a theoretical reference for the pharmaceutical synthesis.
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (MTb).The World Health Organization estimates that one third of the world’s population is infected by Mycobacterium tuberculosis. Each year, there are about 8 million new TB cases and 2 million deaths worldwide. TB was declared a global health emergency by the WHO in 1993 and 2004 respectively. In this paper, the quantitative structure-activity relationship studies on 6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid derivatives, The QSAR results can provide theoretical reference for syntheticing such drugs with a higher antimicrobial activity.
Non steroidal anti-inflammatory drugs are the first line therapy for the treatment of arthritis and block the metabolism of arachidonic acid through inhibition of cyclooxygenase and thereby production of prostaglandins (PGs). Cyclooxygenase-2 is not expressed in most of normal tissues, but it is synthesized rapidly to take part in inflammation course and oncogenesis when cells are stimulated by various kinds of stimuli, such as cytokines, inflammatory agent and induced by carcinogenic agent. Further and thorough research on cyclooxygenase-2 will provide a new target for new non-steroidal anti-inflammatory drugs. In this paper, we build the quantitative relationship between drug activities with the structure of 1, 2-diaryl imidazole as cyclooxygenase-2 selective inhibitor, the calculated parameters effect on antibacterial activity was discussed in detail based on the QSAR results, providing theoretical guidance for finding highly active non steroidal anti-inflammatory drugs.
本论文运用偏最小二乘回归、穷举回归和混沌遗传神经网络方法分别对醛糖还原酶抑制剂、趋化因子受体5(CCR5)拮抗剂、6-氟-4-氧-1, 4-二氢喹啉-3-羧基衍生物抗菌活性和环氧合酶-2选择性抑制剂四个体系进行了定量构效关系研究。
糖尿病是一种严重危害人们健康的常见慢性疾病,在导致人类死亡的疾病中居第三位,仅次于心脑血管疾病和肿瘤,其慢性并发症是糖尿病致死致残的主要原因。经研究证明,醛糖还原酶活性增高是导致糖尿病慢性并发症的主要原因之一,因此抑制醛糖还原酶活性成为治疗糖尿病并发症的一种策略。本章就2,4-噻唑烷二酮类化合物作为醛糖还原酶抑制剂进行了QSAR研究,为寻找高活性抗炎药物提供理论指导。
人类获得性免疫缺陷综合症—艾滋病主要是由于人类免疫缺陷病毒1型(HIV-1)病毒感染,在体内快速繁殖并导致宿主白细胞的大量破坏所致。世界各地都在努力防止HIV-1的扩散,但艾滋病毒的感染者人数仍继续上升。CCR5,作为G蛋白偶联因子超家族(GPCR)成员的细胞膜蛋白,是HIV-1入侵机体细胞的主要辅助受体之一,以CCR5为靶点的HIV-1受体拮抗剂越来越受关注。本章对CCR5拮抗剂进行了定量结构活性关系研究,期待为实验工作者合成新药提供理论参考。
结核病是由结核分枝杆菌感染所致,困扰人类已有数千年之久。世界卫生组织统计约1/3的世界人口被结核病感染,全球每年约800万新结核病例和200万死亡患者,并于1993年和2004年两度发布“全球结核紧急状态”预警。本章对51个6-氟-4-氧喹啉-3-羧基衍生物进行了定量结构活性关系研究,以期为设计合成更高抗菌活性的该类药物提供理论参考。
非甾体抗炎药具有抗炎、解热、镇痛等作用,在临床上被广泛用于治疗类风湿性关节炎、骨关节炎等疾病,该类药物通过抑制环氧合酶阻断前列腺素的生物合成而起作用。环氧合酶-2在大多数正常组织中不表达,但在细胞受到各种刺激,如细胞因子、炎症因子、促癌剂等的诱导下会迅速合成,参与炎症过程和肿瘤的发生。因此,对环氧合酶-2的深入研究将为合成新的非甾体抗炎药提供新的靶点。本章建立了1,2-二芳基咪唑类环氧合酶-2选择性抑制剂药物活性与其结构的定量关系模型,根据研究结果讨论了计算的参数对抗菌活性的影响,为寻找高活性抗炎药物提供理论指导。
Quantitative structure-activity relationship (QSAR) is a method of predicting molecular chemistry characteristics from the parameters of physical-chemical and molecular structure. QSAR researches the molecule simulation, which based on quantum chemical computation, were combined to offer a new route to seek several precursor compounds with biologic and medical activity. With quantitative structure-activity relationship analysis, it is possible to analyze the probable structural elements affecting the biological activity of compounds. The information can be used in designing new bioactive compounds and exploring the mechanism of drugs.
In this thesis, the QSAR studies for antimycobacterial activity of aldose reductase inhibitors, chemokine receptor antagonist, 6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid derivatives, selective inhibitor of cyclooxygenase-2 were carried out by using partial least-squares regression, exhaustive linear regression and chaos genetic neural network. According to these models, we discussed the effects of these parameters on inhibitory activity.
Diabetes is a chronic disease which is very harmful to people’s health. It is the third factor leading human to death, inferior to cardiovascular diseases and tumor. Diabetes control and complications is the main reason for diabetes death and disability. The studies have shown that the increased activity of aldose reductase leading to diabetes control and complications, so inhibiting aldose reductase can be a strategy for diabetic complications. We herein describe analysis of 2, 4-thiazolidinediones as inhibitors of aldose reductase.The relevance of the QSAR model obtained for the design of novel derivatives should be assessed not only in terms of predictivity, but also in terms of their ability to provide a chemical and structural explanation of their binding interaction. The results obtained here will be useful for the design of new aldose reductase inhibitors.
The human acquired immunodeficiency syndrome (AIDS) is mainly due to human immunodeficiency virus type 1 (HIV-1) infection, which is rapid propagation of the body and lead to damage huge amount of white blood cells. Despite worldwide efforts to prevent the spread of HIV-1, the number of HIV-1 infected people still continues to rise. CCR5, a membrane protein on cell surface, is a member of G protein-coupled receptor superfamily and one of the major co-receptors for HIV-1 infection was received with excitement in the scientific community as a potential new target for antiviral therapy. In this paper, the quantitative structure-activity relationship studies on CCR5 antagonist, according to the results of QSAR studies, we put forward a number of high activities of CCR5 antagonist in theory, and look forward to experimental confirmation. The QSAR results can offer a theoretical reference for the pharmaceutical synthesis.
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (MTb).The World Health Organization estimates that one third of the world’s population is infected by Mycobacterium tuberculosis. Each year, there are about 8 million new TB cases and 2 million deaths worldwide. TB was declared a global health emergency by the WHO in 1993 and 2004 respectively. In this paper, the quantitative structure-activity relationship studies on 6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid derivatives, The QSAR results can provide theoretical reference for syntheticing such drugs with a higher antimicrobial activity.
Non steroidal anti-inflammatory drugs are the first line therapy for the treatment of arthritis and block the metabolism of arachidonic acid through inhibition of cyclooxygenase and thereby production of prostaglandins (PGs). Cyclooxygenase-2 is not expressed in most of normal tissues, but it is synthesized rapidly to take part in inflammation course and oncogenesis when cells are stimulated by various kinds of stimuli, such as cytokines, inflammatory agent and induced by carcinogenic agent. Further and thorough research on cyclooxygenase-2 will provide a new target for new non-steroidal anti-inflammatory drugs. In this paper, we build the quantitative relationship between drug activities with the structure of 1, 2-diaryl imidazole as cyclooxygenase-2 selective inhibitor, the calculated parameters effect on antibacterial activity was discussed in detail based on the QSAR results, providing theoretical guidance for finding highly active non steroidal anti-inflammatory drugs.
引文
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