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Small-molecule drugs and Enzyme target

There are ~1,500 small molecule drugs currently marketed, accounting for ~ 80% of total FDA-approved drugs. Small-molecule drugs target 317 kinds of enzymes, which is ~ 22 % of the total drug targets. Thus, developing of small-molecule inhibitors or activator for enzymes is essential for treatment of diseases.
Our laboratory use biochemistry, computer-aided drug design and high throughput screening and other research tools to discover small molecule modulators of enzymes, aiming for developing drug leads and chemical tools for the relevant diseases. These agents can be used as a drug lead for the treatment of disease, and chemical probes for clarifying the underlying mechanism of diseases.
Currently, our lab has identified several selective and bioactive small-molecule inhibitors for a variety of enzymes involved in cancer, Alzheimer’s disease and Parkinson’s disease. For example, the first specific and bioactive inhibitor of CBS (a vitamin B6 -dependent enzyme) has been discovered for combating cancer (Zhou Y. et al, Chem Comm 2013); the natural product based inhibitors for Parkinson 's disease drug target DDC (B6 enzyme; Ren J. et al, ACS Chem Biol, 2014, Cover Story); the smallest inhibitor for gamma-secretase, a protein target for Alzheimer’s disease (Wu F. et al, FASEB J 2010).


High-throughput drug screening model

High-throughput drug screening in the pharmaceutical industry is currently widely used, and is the commonly used method to find drug leads. For example, the drug star Gleevec was screened out by this approach. Constructing innovative drug screening model is the essential for high-throughput drug screening. We constructed several targeted-based high-throughput screening models for a few diseases, including cancer, Alzheimer's disease, Parkinson's diseases, autoimmune diseases, hypertension and other diseases. Apart from the innovative models, we also collected 40,000 small molecules, including 4,000 special natural products from Chinese plants or animals.


The enzymes that produce gaseous signaling molecules e.g. NO, CO and H2S, is considered to be potential drug targets. In the past, high-throughput method for the detection of gas is absence, thus no specific inhibitors or activators have been found. To monitor the activity of hCBS or hCSE, the H2S gas generating enzymes, in a high-throughput mode, we designed a tandem-microwell-based assay for measuring H2S production. The newly designed 192-tandem-well plate was remodeled from a conventional 384-well assay plate by interconnecting each two adjacent wells with a channel in the upper part of the interjacent wall to allow gas exchange. In this arrangement, the gas generated in the well containing the enzymatic reaction solution is simultaneously trapped and quantified in the adjacent well (Fig. 1). The tandem microwell obviates any interference of the analytical reagent with the enzyme(s) and its (their) substrate(s). (Zhou Y. et al, Chem Comm 2013). By using this screening model, we have successfully identified the first selective inhibitor for CBS.

New enzyme substrates and signaling pathway

Protein degradation in cells is a complex biological process and important issue. Transmembrane protein is also to be cut into fragments in the cell membrane and the cytoplasmic fragment sometime translocated into the nucleus, which plays a transcriptional regulatory mechanism. The whole process is called membrane regulated proteolytic cleavage (Regulated Intramembrane Proteolysis, RIP). In mammalian cells, gamma-secretase is responsible for the RIP process. APP protein is an important membrane protein for Alzheimer’s disease, and cleavaged by gamma-secretase in the membrane.

Our laboratory uses small molecular chemical tools, the molecular genetics tools, cell biology methods, to discover the new substrates for gamma-secretase and study the new function of the cellular fragment of the new substrate. It could offer new insights to the underlying mechanisms of complex disease, including Alzheimer’s disease.

Enzyme function and chemical biology research
The catalytic mechanism of the enzymes, as well as their roles in the cellular metabolism and signal pathway, remains largely unknown. Studying of these unknown issues is important. We use small-molecular probes and chemical biology methods to tackle these problems. Using structurally diverse small molecules, combined with molecular modeling and enzyme kinetics method, to reveal enzyme substrate binding and catalytic mechanism; using high affinity/covalent labeling method to find the new target for disease and enzyme active sites; using small-molecular probes to investigate the new functions of signaling pathway and protein post-modifications.

Copyright: 2013 Young Scientist Laboratory of Shanghai Jiaotong University       Technical Support: Shanghai Yi-chao Information Technology Co., Ltd.