National Science Council Project Grant
Project Overview
Natural products have indispensable value in the research and development of drugs and nutritional supplements. The Alliance combines a unique natural product extract library and high-throughput screening technology to bring new niches to the development of natural products. Our core technology focuses on natural product extract preparation, screening, and evaluation of biological activity, and is committed to the development and optimization of new drugs and health supplements. In order to meet different needs, the Alliance provides a full range of technical consultation, information sharing, talent training and cross-domain cooperation, hoping to promote the upgrading and development of the entire industry and provide more contributions to the natural product industry.
Natural products are still an important source of new drug development
Natural products have always been an important source of drug development. In the era when the human genome had not yet been decoded and high-throughput screening technology had not yet been developed, more than 80% of new drugs came from natural products or natural product derivatives. However, with the development of high-throughput technology, new drug development has shifted to small molecule chemical synthesis drug libraries based on combinatorial chemistry. Combinatorial chemistry can quickly provide a large number of small molecule compounds. The number of small molecule compounds contained in this type of drug library is often more than 10,000, or even hundreds of thousands. Therefore, in the 1990s, the proportion of new molecular entities (NMEs) approved by the US FDA that came from natural products decreased significantly. However, past practical experience has also found that the success rate of small molecule compound libraries produced by combinatorial chemistry combined with high-throughput screening strategies in lead drug development does not seem to be proportional to the development resources invested by pharmaceutical companies. The results of many large-scale screens have been disappointing, and researchers have come to understand that the diversity of chemical space relevant to biological activity is more important than the size (number of compounds) of the chemical library.
In addition, an analysis of new drugs approved by the FDA from 1984 to 2014 found that even though the new drug development strategy during this period tended to focus on pure chemical synthetic small molecule drugs, the proportion of pure chemical synthetic small molecule new drugs was still only 27%; in contrast, natural products, natural product derivatives, or synthetic small molecule drugs whose pharmacophore structures are derived from or derived from natural products, and other natural product-related new drugs, plus plant new drugs (usually a mixture of several compounds), accounted for about 51% of the total. This result also shows that natural products are still irreplaceable resources in new drug development. One of the decisive factors is that natural products have diverse pharmacophores and highly complex stereochemistry. Such characteristics also allow natural products to occupy a place in new drug development.
The dilemma of traditional natural medicine development
Although natural products are still an important source of new drug development, the energy of traditional natural product drug development is still far from that of small molecule chemical synthesis drug libraries using combinatorial chemistry combined with high-throughput screening. Generally speaking, researchers must collect enough plant materials in the wild, and after returning to the laboratory, they first prepare crude extracts. At this stage, researchers usually need to send the crude extracts to other laboratories for biological activity testing. The biologically active crude extracts will then be separated and extracted for biological activity-oriented separation to track the stratification of active ingredients. In addition to the mutual cooperation between the natural extraction team and the biological activity testing team, there is also a certain element of luck, so that sufficient potential target compounds can be obtained stably. These research works require a lot of manpower and time, and the full coordination of the two teams is needed to overcome various difficulties and truly apply the research and development results to clinical practice. On the other hand, high-throughput drug screening is a way to quickly find effective active ingredients, but the traditional natural product extraction method, after consuming a lot of manpower and time, can only obtain a very limited number of pure compounds. Moreover, the vast majority of pure compounds are too scarce after purification, which is not enough to cope with the construction of drug libraries and subsequent verification experiments. Therefore, drug libraries composed of natural pure compounds are quite rare, and these drug libraries usually have only a few hundred types of compounds; in addition, the compounds contained in these drug libraries are mostly chemical skeletons that are more abundant in plants or more common. It is also very difficult to repeatedly separate low-content secondary compounds from the same plant sample. In addition, due to the highly complex stereochemical properties of natural products, the yield of natural product synthesis is greatly reduced, and the number of synthetic steps and difficulty are greatly increased. These factors make it difficult to develop new natural product drugs using high-throughput screening.
New opportunities for natural products in the development of new drugs
In order to strike a balance between chemical diversity, drug library size, and the various costs of drug library preparation, the concept of compromise was born, and researchers began to use fractionated extracts (fractions) for high-throughput screening. The crude extract is further divided into dozens to hundreds of fractions. Since a small amount of preparation is sufficient for drug library construction, the scale is miniaturized and the preparation speed is increased. These drug libraries are also very suitable for high-throughput screening for biological activity testing. Such drug libraries, combined with sensitive nuclear magnetic resonance technology, can solve the bottleneck problem of compound separation and structural analysis.
Accelerating the development of natural medicines using tandem mass spectrometry combined with GNPS molecular network analysis
Since the late 1960s, mass spectrometry has been widely used to detect metabolites in biological specimens. Non-standard tandem mass spectrometry is currently one of the main strategies used to discover and annotate new metabolites in metabolomics research. Non-standard tandem mass spectrometry can detect the chemical characteristics of all ionized compounds in a mixed sample. The so-called "chemical characteristics" refers to the molecular ion peak spectrum of all fragments produced after each compound is impacted. Compounds with similar structures will produce the same fragments after collision, and the same molecular ion peak spectrum will appear in mass spectrometry analysis. Therefore, based on the "chemical characteristics" of these mass spectral results. These features can be used to perform similarity comparisons, classify the compounds in the mixed sample according to their structure, analyze the relationships between each compound, and then present them in a network-linked visual format to generate the so-called "molecular network." This analysis, combined with the results of the mixed sample activity analysis, will further identify the compound group that is the source of activity; at the same time, it can also be compared with existing public mass spectrometry databases to identify known compounds and thus identify new active compounds.