“计算中药学”在中药药性及复方研究中的应用
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摘要
中药物种的多样性和多元性,中药成分的丰富性和复杂性,中药配伍的灵活性和多变性,中药信息资源的急剧增长和海量资料的挖掘和整理,中药研究现有实验技术的局限和不足等等,决定了中药研究不可想象的复杂性和艰巨性。我们认识到要正确理解构成中药复杂系统的要素(组成成分)、要素间的相互作用及其个体和整体的效应,需要改变常规的思维方式,在现有的医药学实验科学方法的基础上,应用计算科学及其方法,处理中药研究中关键的科学问题。因此,本论文提出了“计算中药学”这一新的学科概念。“计算中药学”致力于计算、信息技术在中药研究领域的应用,对常规实验无法触及的领域和由来己久的技术难题给出合理而独具特色的研究思路与方案,对中医药领域的抽象概念和高度概括的理论讲述给出科学而定量的实验证据。
本论文详细介绍了“计算中药学”的概念内涵、基本原理、研究方法和研究意义。在此基础上,将“计算中药学”具体应用到中药的四气五味、配伍禁忌等中药药性,以及中药复方药效物质基础的研究中,使“计算中药学”的应用与研究更加深入。本论文的主要研究内容如下：
1)中药化学数据库的建立。运用ISIS/Base软件的数据库创建与管理功能,建立了一个中药化学数据库,该数据库以中药药材为单位,包含了各中药的化学成分信息及其二维、三维结构信息。该数据库共计录入常见中药374味,中药化学成分分子约12000多个。
2)中药寒热预测系统的构建。综合运用数据库查询、化学描述符计算、重心处理技术(原创)、支持向量机分类技术构建了一个中药寒热预测系统,预测准确率达到80%以上,可用于民间草药和外国草药寒热性质的预测。同时,该系统对中药寒热性质与其化学成分物化性质之间的联系给出了新的诠释。
3)辛味中药与嗅觉受体相互作用的研究。通过GPCR的同源模建、分子动力学的综合运用,首次构建了三个嗅觉受体的三维模型,并以之为模板与辛味中药的化学成分进行分子对接,发现嗅觉受体的刺激很可能是辛味中药发挥药效的第一个环节,而这种作用是通过正性的激动作用而产生。
4)方剂网络与化学空间对中药配伍禁忌的研究。分别采用复杂网络技术和化学空间技术构建了中药方剂网络和中药化学空间,并将其运用到中药方剂配伍禁忌的分析之中,对“十八反十九畏”配伍禁忌的经验法则给出了科学的解释。
5)复方血必净治疗脓毒症的药效物质基础研究。绘制并分析了脓毒症发病机制的效应网络,从中挑选出关键的病理靶点,运用虚拟筛选技术对复方血必净治疗脓毒症的药效物质基础进行了全面的搜索和筛选,最后找到数个颇有潜力的单体分子,将用于将来的生物实验筛选和验证。本论文结构层层递进,内容由浅入深,通过系统宏观的理论论述和深入细微的实例研究,展现“计算中药学”的内涵与外延,理论与应用。相信,随着研究的深入和方法学的完善,“计算中药学”将广泛应用到中药研究的各个方面,为中药现代化的进步贡献一份力量。
Chinese Materia Medica (CMM) are characterized as the diversity and pluralism on their species, richness and complexity on their ingredients, flexibility and variability on their compatibility. Information resources of CMM are sharply rising nowadays, and the accumulative data need to mine and abstract. But the methodologies and technologies are limited in the studies of CMM at present. All of these make the CMM study a tough mission with tremendous difficulty and complexity. In order to understand the complexity of CMM and the relationship between CMM and their ingredients, it is necessary to change our thinking mode, and apply computational sciences to solve the key problems of CMM based on the current experimental methodologies. Therefore, a new concept, Computational Chinese Materia Medica (CCMM), was proposed in this dissertation. CCMM applies the methodologies and technologies of computing and information sciences to the field of CMM study, and supplies fresh ideas and reasonable solutions on the problems that failed by conventional experiments, and offers quantitative and scientific evidences for the abstract concepts and theories in the field of Traditional Chinese Medicine (TCM).
The concept, theory and methodology of CCMM were introduced in detail in this dissertation firstly. And then, the application studies of CCMM on CMM Properties and TCM Prescriptions were shown in different sections. The research programs in this dissertation were listed as follow.
1) Construction of CMM chemical database. We used ISIS/Base, a piece of software for database creation and administration, to create a CMM chemical database, which contains 374 common CMM and 15000 chemicals in CMM. All the chemicals have their 2D and 3D structures stored in the database.
2) Creation of prediction system for CMM hot/cold properties. A prediction system for CMM hot/cold properties was created by using CMM chemical database, descriptor calculation, weight center treatment (original method) and support vector machine classification. The prediction accuracy of this system is over 80%, which ensures its application to the hot/cold properties prediction of folk and foreign herbs. Besides, the descriptors derived from this system have given the help on interpretation the relationship between hot/cold properties of CMM and their chemical ingredients.
3) The study of interaction between pungent CMM and olfactory receptors. The three-dimensional structures of three typical olfactory receptors were constructed for the first time by using homology modeling and molecular dynamics simulation method. The interaction between pungent CMM and these olfactory receptors has been researched by molecular docking. It's inferred that the action of pungent CMM is probably involved with the activation of olfactory receptors as the first step.
4) The study of incompatibility property of CMM through TCM formula network and chemical space. A TCM formula network was built by using complex network methodologies. Topology analysis was preformed based on this network. Meanwhile, we built a TCM chemical space and performed some analyses. "Eighteen antagonisms and nineteen mutual inhibitions", the ancient theory of TCM prescription incompatibility, was interpreted in modern scientific language through the network pathway distance analysis and the chemical space distance measurement based on the theory of complex networks and chemical space, respectively.
5) Studies on the effective materials of Xuebijing towards Sepsis treatment. We drew maps on the network effects of sepsis, and selected a series of key protein targets involved. The effective materials of Xuebijing, a TCM prescription, were searched by virtual screening. Several compounds have been found at last, and they will be tested by bio-experiments in the future.
This dissertation gives the concept of the CCMM and its application studies through theory demonstration and case researches. We believe CCMM will be widely used in all aspects of CMM researches as methodology improving and study deepening, and make a contribution to the progress of modernization of TCM
本论文详细介绍了“计算中药学”的概念内涵、基本原理、研究方法和研究意义。在此基础上,将“计算中药学”具体应用到中药的四气五味、配伍禁忌等中药药性,以及中药复方药效物质基础的研究中,使“计算中药学”的应用与研究更加深入。本论文的主要研究内容如下：
1)中药化学数据库的建立。运用ISIS/Base软件的数据库创建与管理功能,建立了一个中药化学数据库,该数据库以中药药材为单位,包含了各中药的化学成分信息及其二维、三维结构信息。该数据库共计录入常见中药374味,中药化学成分分子约12000多个。
2)中药寒热预测系统的构建。综合运用数据库查询、化学描述符计算、重心处理技术(原创)、支持向量机分类技术构建了一个中药寒热预测系统,预测准确率达到80%以上,可用于民间草药和外国草药寒热性质的预测。同时,该系统对中药寒热性质与其化学成分物化性质之间的联系给出了新的诠释。
3)辛味中药与嗅觉受体相互作用的研究。通过GPCR的同源模建、分子动力学的综合运用,首次构建了三个嗅觉受体的三维模型,并以之为模板与辛味中药的化学成分进行分子对接,发现嗅觉受体的刺激很可能是辛味中药发挥药效的第一个环节,而这种作用是通过正性的激动作用而产生。
4)方剂网络与化学空间对中药配伍禁忌的研究。分别采用复杂网络技术和化学空间技术构建了中药方剂网络和中药化学空间,并将其运用到中药方剂配伍禁忌的分析之中,对“十八反十九畏”配伍禁忌的经验法则给出了科学的解释。
5)复方血必净治疗脓毒症的药效物质基础研究。绘制并分析了脓毒症发病机制的效应网络,从中挑选出关键的病理靶点,运用虚拟筛选技术对复方血必净治疗脓毒症的药效物质基础进行了全面的搜索和筛选,最后找到数个颇有潜力的单体分子,将用于将来的生物实验筛选和验证。本论文结构层层递进,内容由浅入深,通过系统宏观的理论论述和深入细微的实例研究,展现“计算中药学”的内涵与外延,理论与应用。相信,随着研究的深入和方法学的完善,“计算中药学”将广泛应用到中药研究的各个方面,为中药现代化的进步贡献一份力量。
Chinese Materia Medica (CMM) are characterized as the diversity and pluralism on their species, richness and complexity on their ingredients, flexibility and variability on their compatibility. Information resources of CMM are sharply rising nowadays, and the accumulative data need to mine and abstract. But the methodologies and technologies are limited in the studies of CMM at present. All of these make the CMM study a tough mission with tremendous difficulty and complexity. In order to understand the complexity of CMM and the relationship between CMM and their ingredients, it is necessary to change our thinking mode, and apply computational sciences to solve the key problems of CMM based on the current experimental methodologies. Therefore, a new concept, Computational Chinese Materia Medica (CCMM), was proposed in this dissertation. CCMM applies the methodologies and technologies of computing and information sciences to the field of CMM study, and supplies fresh ideas and reasonable solutions on the problems that failed by conventional experiments, and offers quantitative and scientific evidences for the abstract concepts and theories in the field of Traditional Chinese Medicine (TCM).
The concept, theory and methodology of CCMM were introduced in detail in this dissertation firstly. And then, the application studies of CCMM on CMM Properties and TCM Prescriptions were shown in different sections. The research programs in this dissertation were listed as follow.
1) Construction of CMM chemical database. We used ISIS/Base, a piece of software for database creation and administration, to create a CMM chemical database, which contains 374 common CMM and 15000 chemicals in CMM. All the chemicals have their 2D and 3D structures stored in the database.
2) Creation of prediction system for CMM hot/cold properties. A prediction system for CMM hot/cold properties was created by using CMM chemical database, descriptor calculation, weight center treatment (original method) and support vector machine classification. The prediction accuracy of this system is over 80%, which ensures its application to the hot/cold properties prediction of folk and foreign herbs. Besides, the descriptors derived from this system have given the help on interpretation the relationship between hot/cold properties of CMM and their chemical ingredients.
3) The study of interaction between pungent CMM and olfactory receptors. The three-dimensional structures of three typical olfactory receptors were constructed for the first time by using homology modeling and molecular dynamics simulation method. The interaction between pungent CMM and these olfactory receptors has been researched by molecular docking. It's inferred that the action of pungent CMM is probably involved with the activation of olfactory receptors as the first step.
4) The study of incompatibility property of CMM through TCM formula network and chemical space. A TCM formula network was built by using complex network methodologies. Topology analysis was preformed based on this network. Meanwhile, we built a TCM chemical space and performed some analyses. "Eighteen antagonisms and nineteen mutual inhibitions", the ancient theory of TCM prescription incompatibility, was interpreted in modern scientific language through the network pathway distance analysis and the chemical space distance measurement based on the theory of complex networks and chemical space, respectively.
5) Studies on the effective materials of Xuebijing towards Sepsis treatment. We drew maps on the network effects of sepsis, and selected a series of key protein targets involved. The effective materials of Xuebijing, a TCM prescription, were searched by virtual screening. Several compounds have been found at last, and they will be tested by bio-experiments in the future.
This dissertation gives the concept of the CCMM and its application studies through theory demonstration and case researches. We believe CCMM will be widely used in all aspects of CMM researches as methodology improving and study deepening, and make a contribution to the progress of modernization of TCM
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