Our lab is focused on the interface of biocatalysis, natural product biomimetic synthesis and biologically valuable molecule discovery. We are encouraged by the rapid and efficient construction of molecular complexity from simple precursors in living organisms by enzymatic pathway. On the microcosmic molecular level, enzyme catalyzed organic bond formation provided fundamental details of the molecular activation between catalyst and substrates through either non-bonded or covalent-bonded interactions. Inspired by the three-dimensional structure of the active binding residues of the enzyme pocket, we are interested in developing organic small molecule catalyst for stereoselective construction of chemical bonds that otherwise tough to access. Privileged coordination of transition structure geometries and molecular recognition that control selectivity will be explored in details by computational calculation and chemical kinetics. The utility of these small molecule catalysts will be demonstrated by the synthesis of a variety of important biologically interesting compounds through environmentally friendly organocascade process that involve the formation of several chemical bonds and stereogenic centers simultaneously with excellent stereoselectivity. Structurally complex natural products are naturally produced in microorganisms through a series of elaborate biological pathways, so its biomimetic synthesis will be incorporated with organocascade catalysis in the lab. Besides discovery of small molecule catalysis and natural product biomimetic synthesis, we are also interested in developing novel reagents for practical transformations to rapidly assemble unnatural complex molecules. The combination of chemical synthesis and biosynthesis of biologically valuable molecules is an important part of our pursuits for exciting discoveries of biomaterials, chemical biology as well as pharmaceutical agents to solve serious health problem in living system.
Overall, the inspiration from natural living system to develop small molecule catalyst, organocascade assembling of complex molecule will eventually result in discovery of novel bio-valuable molecules, which in turn serve as significant regulatory tools for a variety of biological pathways in living system. During this conceivably “functional cycle”, small molecule and living organism can be thought of as complementary forces that interact to form a dynamic system in which each could promote mutually by the other. We presumptively demonstrate this as “Functional Reincarnation of Organic Molecule”, thereupon we bear persistent enthusiasm for the pursuit of ideal discovery of novel molecules and interpretation their bioactive mechanism of act.
Total Synthesis of Natural Product and Bioactive small molecule development. The use of small molecules to probe systematic and disease-associated biological phenomena is an important aspect of our research. Motivated by the urgent and valuable applications of small molecules in therapeutics and biomedical research, we are devoted to synthesizing new organic, inorganic, and organometallic molecules that applicable to a wide variety of biological areas conducted at NIBS. Our focus is on the design and execution of syntheses that deliver diverse small molecules in a highly efficient manner therefore promote and strengthen the basic life science at NIBS. The generation of new synthetic assembly of small molecule and enriching the molecule library is one of central focuses within the lab. We are working on the molecule discovery and collection through synthetic method development with the aim of expanding chemical diversity in novel ways. We also undertake synthesis of newly identified valuable molecules through highly efficient strategies for novel function exploration.
Molecules synthesized in the our lab are inherently integrated for the purpose of examining their biological properties. The outcomes of this biological evaluation and the performance in biological screening are the main guidance for further synthesis design. After a range of chemicals is screened against a particular drug target or disease model, and the qualified “hits” chemicals are concentrated and analyzed. Commonalities among the different chemical groups are studied as they are often reflective of a particular chemical subunit. Additional chemical synthesis will be enforced to extend out the chemical library through “activity-oriented synthesis” in that particular subspace by generating more compounds with subtle and profound modifications. This new selection of compounds within this narrow range are further investigated and then taken on to more sophisticated models for further validation. Chemical compounds need to satisfy a variety of constraints before they become pharmaceutical candidate, including solubility, oral bioavailability, cell membrane permeability, liver enzyme activity, plasma protein binding, penetration of the blood-brain barrier, toxicity, and many others. We are focusing on the structure design to improve molecular properties that are not limited to Lipinski’s rules.
High-Throughput Screening (HTS):
HTS is a drug-discovery process widely used in the pharmaceutical companies and biomedical research institutes. Using robotics, data processing and control software, liquid handling devices and sensitive detectors, HTS conduct extremely scalable assay to test the biological or biochemical activity of a large number of small molecules for discovering active agents for receptors, enzymes, ion-channels or other pharmacological targets in the molecular and cellular level of biomolecular pathway. Typically, HTS assays are performed in microtiter plates with a 96 or 384 well format. HTS is one of main facilities in our lab to provide comprehensive services including the use of HTS technology, compounds in various libraries, a database of results from screens and lead optimization. On a collaborative basis, HTS has the capability to support cellular and biochemical assays using absorbance, fluorescent kinetics, fluorescence resonance energy transfer, AlphaScreen, bioluminescence and cellular fluorescence imaging. In addition, HTS has expertise in adapting those biological and biochemical bench-top assays into high-throughput screening settings. HTS libraries are designed for diversity around specific pharmacophore, they often use molecular property profiles in the design process. Encouraged by the fact that a significant number of marketed drugs are derived from natural products and the fact that the distribution of molecular properties found in a HTS library was rather narrowly defined compared to natural products and marketed drugs, we are also interested in expanding natural chemical products in compound libraries and developing effective strategy to diversify the core backbone structure of natural products. According to current natural product isolation progress, we will select highly active small molecules targeting at serious diseases therapy. We will design and explore biomimetric synthetic pathways to build up the molecule efficiently. Easily modified structure and high selective strategy will be preferred. The organocascade type assembling of complex structure will eventually result in the discovery of novel bio-valuable molecules to diversify the library of natural products analog.