Generally speaking, new situation was opened up for drug discovery when modern science has got a lot of progress in biotechnology, such as the high throughput screening, combinatorial synthesis, asymmetric synthesis, et al. But the pharmaceutical industry is still facing serious challenges because the drug discovery has become more expensive, more risk and lower efficiency. Therefore, a significant change that focus shift from single-target drugs to multi-target drugs have been occurring based on the knowledge of traditional medicine. Strategic choice which based on the drug discovery from natural products, ethnic pharmacology and traditional medicine is expected to overcome the main obstacle that caused by three factors of time, cost, and toxicity during the previous drug discovery. It has been coming to the fore as another drug discovery engine. New strategic choice spawned an interdisciplinary research field called reverse pharmacology [3
] which provides a paradigm shift from random tracking accidental discovery to organizing a route for seeking lead compound in drug development.
In the study of reverse pharmacology, traditional drugs which have been proved curative in the long-term medical practice were selected for exploratory research aimed at standardization and safety. The confirmation of traditional drugs in the different biological levels, the clarification of its pharmacological mechanism and the identification of its corresponding active components or effective substance will provide scientific basis for the clinical application of traditional drugs, lay the foundation for safety assessment and quality control of traditional drugs, find new leads for creating new chemical drugs and turn the leads to drug candidate through preclinical and clinical research. In this process, safety is the most essential starting point and the effect becomes a thing to be confirmed. Previous "laboratory - clinical" mode in the drug discovery process was reversed to "clinical - laboratory" by reverse pharmacology inspired by the traditional knowledge. The innovativeness of this research mode is that combines the traditional knowledge and modern science and technology, to provide better and safer lead compounds more efficiently. Thus, the traditional herbal medicines which have appeared high efficacy and low side effects in long-term clinic practice got more attention.
The traditional medicine, a rich resource to obtain new lead compounds, generally has complex and diverse chemical composition. In case of analgesic drugs, based on past clinical experience and experimental observation, single herb analgesic are rhizoma ligustici wallichii [10
], corydalis [11
], panax notoginseng [12
], radix angelicae pubesentis [13
], clematis [14
], etc. However, the analgesic activity component of these herbs has few developments so far. One reason for this situation is although these drugs and their ingredients have analgesic effect, the mechanism and targets have been not elucidated in the modern technological level. Another reason is which ingredients produce the analgesic effect of original drug has not been confirmed as the original drug is a mixture of a variety of chemical constituents and it usually has a variety of pharmacological effects.
Different from single chemical entity drugs, the pharmacological study of traditional medicine need not only clarify the pharmacological mechanism of the traditional drug but also identify the effective substances which produce specific pharmacological effects. The mechanism of the pharmacological effects was revealed by identifying the effective substances, while identifying the effective substances depend on clarifying the pharmacological mechanism of the traditional drug. This is a key issue that clarify scientific basis of clinical curative effect of traditional medicine through the correlation of effective substances and pharmacological mechanism. This is also a methodology question about how to get lead compounds which can reflect original drug’s good performance.
Usual research method of traditional drug is the effects of the chemical composition of the original drug and those of the original drug itself were studied separately. This method do not link the effects of the original drug and its composition, and do ignore a problem that the effect of the original drug and its composition may not be completely consistent, which should give full attention in the research of traditional drug. Therefore, the past method does little help to clarify the pharmacological mechanism of the original drug and to identify the compositions which have the specific pharmacological effect of the original drug and its degree. It is more difficult to determine whether the isolated compositions still retain the relationship between the ingredients in original drug when they produce specific pharmacological effect (Few studies on the combined effects of ingredients in original drug). Aiming at these unsolved questions in research and development of traditional medicine, based on the biological background of traditional medicine Resina Draconis
, the basic principle of reverse pharmacology methodology that seeking the component/combinations as primer of new drug should compare the effects of the component/combination with those of the traditional medicine itself with the reference of the pharmacological effects of the traditional medicine were put forward.
In order to solve the problem, the operational definition of the material basis for the efficacy of traditional drug was established as follows [15
]. If some component/combination extracted from the traditional drug could produce some pharmacological effect which could also be produced by the traditional drug, the component/combination can be regarded as the effective component/combination of the traditional drug corresponding to the pharmacological effect (We’d like to point out that the concept of active component is used particularly to refer to the component extracted from nature medicine with some pharmacological effects). When the quantity of the effective component/combination is correlative with the quantity of the component/combination contained in the traditional drug and when the pharmacological effect of the effective component/combination could replace that of the traditional drug, the effective component/combination can be named as the material basis for the efficacy of the traditional drug. Whether the traditional drug and its component/combination have pharmacological effects is determined by the values of their pharmacodynamic parameters. The effective degree of the component/combination is determined by the degree of agreement between the values of pharmacodynamic parameters of the component/combination and those of the traditional drug. According to the operational definition, a corresponding research strategy was designed: when the material basis for the efficacy of the traditional drug corresponding to some pharmacological effect is identified, the pharmacological research on the traditional drug should be combined with that on its component/combination. Besides, the study of material basis and the research on pharmacological mechanism of the traditional drug should also be combined. The pharmacological effect of the traditional drug as a whole should be identified first, and by using it as the reference, whether the examined component/combination of the traditional drug has similar effect should be subsequently identified. And then the values of pharmacodynamic parameters of the component/combination should be compared with those of the traditional drug. The comparison determines whether the component/combination is the effective component/combination or the material basis for the efficacy of the traditional drug. Conforming to the operational definition, the component/combination whose pharmacological effect could embody the pharmacological characteristics of the traditional drug and replace the pharmacological effect of the original traditional drug should be found out from various components of the traditional drug to act as the material basis for its efficacy.
The operational definition of the material basis for the efficacy of the traditional drug reflects the relationship between the pharmacological effect of original drug and that of the component/combination, and it helps to quantitatively characterize effectiveness of the component/combination. By the establishment of operational definition of effective substance, searching for the effective substance of traditional drug was converted to a problem that is how to detect, express and analyze the relationships between the pharmacological effects of the component/combination and the traditional drug itself, which could be solved by modern technology. This strategy makes the drug discovery based on traditional medicine resource can be really implemented. After the introduction of the operational definition of the material basis for the efficacy of the traditional medicine, the research model of reverse pharmacology is as follows. At first, based on the reliable data and clinical observations of the therapeutical effect of the traditional drug, the hypothesis of pharmacological mechanism of the traditional drug should be raised. Aiming at the target, exploratory study was carried out to confirm the effect of traditional drug at the molecular and cellular levels. According to the above operational definition and referring to the effects of the original drug, the component/combination having pharmacological activity were screened out. Through the qualitative and quantitative analysis of the pharmacological effects between the original drug and its component/combination, the material basis for the efficacy of the traditional drug which could replace (or approximation to replace) the original traditional drug can be identified. If the material basis for the efficacy consists of several components, the interaction between the components should also be analyzed. Afterwards, more extensive pharmacological and pharmacodynamic studies on the material basis for the efficacy should be carried out at the tissue, organ and individual levels.
Follow the methodology of reverse pharmacology above, a well-known traditional drug Resina Draconis
which has been proved has good analgesic effect and no significant side effect in the long-term clinical practice was carried out a series of studies.