Strategic Exploration On Discovery Of Natural Small Molecule CFTR Chloride Channel Activators

Modern medicines play key roles in the economic progress and social development today.Innovation drugs research and development is a multidisciplinary process,which manifests the newest achievement in life sciences and biotechnology.In the development of new drug,there are many difficulties to be resolved among which molecular targets and drug library especially important.With the accomplishment of genomic,more and more potential molecular targets have been identified.Emerging of HTS method enables screening large scale of compounds in a short time possible.While the rate of new drug achieved is not as significant as predicted.Many reasons might account for the obviously inefficiency, deficient varieties of compound library can not be ignored.Three kinds of libraries available now:1.Combinatorial small molecule library,combinatorial technique has synthesized millions of chemicals.Due to structure deficiency and bio-safety uncertainty reasons,clinical use of these compounds is difficult.2.Proved drug library.There are thousands of proved drugs used today.Investigation new function of these drugs is one of the most things in drug discovery.But these drugs are owned by few pharmaceutical companies and also have the structure deficiency defects.3. Natural compounds.Traditionally,natural compounds are the main resource of new drug.Many drugs were developed from natural compounds or derivates.Compared to synthetic compounds,natural compounds have many prominent merits:they are more easily to bind to biological macromolecules,particularly proteins.As a result, natural compounds are able to interact with many specific targets within the cell.As the 'chemical space' occupied by natural products is both more varied and more drug-like than that of combinatorial chemical collections,synthetic and biosynthetic methods are being developed to produce screening libraries of natural product-like compounds.While,due to the complicate of natural products,it is difficult to apply to the modern screening assay.A wide coverage,quality controlled,suitable for HTS drug library is of necessary.A renaissance of drug discovery inspired by natural products can be predicted.In this study,a new strategy was proposed based on HTS and traditional Chinese medicine chemistry research platform,in which high-hit rate identification strategy was evaluated by a two-step screening methods.Main constitution of the strategy composed a quality controlled traditional Chinese medicine fraction library constructed from 500 TCM,related information administration software.Among which 24,000 TCM fraction library from 300 TCM has been accomplished.A cell-based fluorescence assay for screening of CFTR activators was used to evaluation the new strategy.Primary screening identified 800 hits.Magnolin was identified from one of the tested TCM that confirmed efficiency of the new strategy.