Research Drug Discovery

Drug Discovery and Chemical Genetics: A Modular Combinatorial Approach

Natural products are rich in biologically active compounds, with structural complexity and diversity unrivaled to even all the combined man-made molecules. Unlike synthetic products, natural products have been thoroughly optimized through selected co-evolution (symbiosis) and taken up specific roles in defending and promoting the fitness of an organism. The role of natural products in modern medicine dated back to the dawn of humanity, where herbs and folklore remedies have been used to treat human diseases. They form an integral part of the present day exploration and development of clinical drugs and crop protection recipes. Approximately 60% of the approved drugs and those in clinical trials are derived from natural origin. Much of this success has been attributed to their structural diversity, which is not accessible by even the modern combinatorial methods, and the specificity and selectivity inherent in their intricate structure. While natural products have made a major impact on human health, their contribution to our understanding of cellular networks is unequivocal. Despite these enormous potentials, application of combinatorial approaches for generating chemical diversity based on the assembly of natural product intermediates has yet to be established. Presently, chemical libraries, even those considered “synthesis of natural-product compound libraries”, are constructed by modifying the various substituents (through removal, addition, or conversion) on a selected scaffold or template. The substituents consist mostly of simple functional groups, containing fewer chiral centers and less elaborated structures. Although a number of biologically active compounds have been discovered this way, libraries with the same scaffold often exhibit the same biological activities and pharmacokinetic properties. Such libraries are thus constrained to a narrow pharmacologic space.

Research Interests

Our group is interested in developing synthetic strategies for incorporating natural-product intermediates into the main stream of combinatorial chemistry, where molecular diversity can be generated in a modular format. Nature has taught us a great deal about molecular assembly and structural diversity. Take nucleic acids, proteins, and oligosaccharides for examples, they form the fundamental basis of all life forms and cover considerable structural space from a very limited number of building blocks. Our group is also interested in developing a multipurpose molecular tag that will resolve the problems of solubility, cellular transduction, and rapid target identification often encountered in drug discovery and chemical genetic efforts. The system under current investigation has the potential to deliver chemical load (drug and so forth) in a temporally and spatially controlled fashion.

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