Structure Bioinformatics, TCM Databases, and Personalized Drug Design

魏冬青 教授


JF Wang 1,2 , T Zhang 1 , J. He 1 , YQ Zhong 1,2 , XJ Wang 1 , Dong-Qing Wei 1*

1 College of Life Science and Biotechnology, Shanghai Jiaotong University , Shanghai 200240, China

2 Bioinformatics Center, Key Lab of Systems Biology, Shanghai Institutes for Biological Science, Chinese Academy of Science, Shanghai 200031, China

Structure bioinformatics tools have been developed to generate 3D structure from sequences of novel genes[1-3]. It allows us pursue structure based drug design. Applications were made to drug design for SARS, H5N1 and HIV. A octapeptide AVLQSGFR designed by us was synthesized and its antiviral potential against SARS coronavirus (BJ-01) was assessed, which demonstrates that AVLQSGFR is the most active in inhibiting replication of the SARS coronavirus compared with other compounds reported so far(EC50 is 2.7×10 -2 mg/L, and its selectivity index is more than 3704), while no detectable toxicity on Vero cells under the condition of experimental concentration is observed.

We have built an effective component Database of the Traditional Chinese Medicine(TCMD)[4], which contains 3-D structures of 10000 different compounds from various sources of traditional Chinese medicines. The database is screened with various cheminformatics tools, many promising molecules were obtained, for example, agaritine was singled out through similarity search and molecular docking method.

Cytochrome P450s are considered as the most important enzymes responsible for the phase I drug metabolism[5-7]. By now, there are over 7700 distinct CYP sequence which can be found in the NCBI database. For their metabolizing more than 90% known drugs, CYP1, 2 and 3 families are of the most importance. The three-dimensional (3D) structure of CYP2E1 has been development by homology modeling methods using the crystal structure of CYP 2C 5 as a guide. Then, a series assessment has been carried out on the computational 3D structure. After a short molecular dynamics, 12 known drugs have been docked to the optimized computational 3D structure using AutoDock. To investigate the interactions of CYP2E1 with substrates, 8ns MD simulations were subsequently carried out. And it is found that Leu368 is of most importance for the interactions of CYP2E1 with substrates. It can provide hydrophobic molecular surface to stabilize corresponding substrates. In addition, Ile115, Phe298 and Val364 are in charge of stabilizing some special substrates. All these findings accord with the results obtained from photo-affinity labeling studies, and will be very useful for conducting mutagenesis studies, providing useful information for drug metabolism and personalization of drug treatments, as well as stimulating novel strategies for finding desired personalized drugs.


•  Suzanne Sirois , Rui Zhang, Weina Gao, Hui Gao, Yun Li and Dong-Qing Wei*, “Discovery of Potent anti-SARS-CoV MPro inhibitors”, Current Computer Aided Drug Design, 3, 341-352(2007).

•  William Kem, Ferenc Soti, Susan LeFrancois, Kristin Wildeboer, Kelly MacDougall, Dong-Qing Wei, Kuo-Chen Chou and Hugo R. Arias, “The Nemertine Toxin Anabaseine and its Derivative DMXBA (GTS-21): Chemical and Pharmacological Properties”, M arine Drugs 4 , 55-273(2006).

•  Kuo-Chen Chou, Dong-Qing Wei, Qi-Shi Du, Suzanne Sirois, Wei-Zhu Zhong, Progress in Drug Development against SARS, Current Medicinal Chemistry, 13 , 3263-3270(2006).

•  Jing-fang Wang, Dong-Qing Wei*, Kuo-chen Chou*, “Drug Candidates From The Traditional Chinese Medicine”, Current Topics Med. Chem, 8 , 156-1665(2008).

•  Cheng-Cheng Zhang, Jing-Fang Wang, DQ Wei et al. , Structure of cytochrome P450s and personalized drug, Current Med. Chem., 16 , 232-244(2009).

•  Jing-Fang Wang , Dong-Qing Wei*, Kuo-Chen Chou, “Pharmacogenomics and Personalized Use of Drugs”, Current Topics in Medicinal Chemistry, 8 , 1573-1579(2008).

•  Jing-Fang Wang, Cheng-Cheng Zhang, DQ Wei et al ., Molecular Modeling of CYP Proteins and Its Implication for Personal Drug Design. “Automation in Genomics and Proteomics: An Engineering Case-Based Approach” to be published by Wiley Publishing, a text book for Harvard and MIT students.

Prof. Dong-Qing Wei is the a cting head, Department of Bioinformatics and Biostatistics, College of Life Science and Biotechnology, Shanghai Jiaotong University , Shanghai , China , e ditor-in-Chief, “Interdisciplinary Sciences- Computational Life Sciences”, chairman, International Association of Scientists in the Interdisciplinary Areas(IASIA). Prof. Wei's research is in the general area of structural bioinformatics. He is best known for his ground-breaking work on theory of complicated liquids. He along with Prof. Gren Patey have found that strongly interacting dipolar spheres can form a ferroelectric nematic phase. This was the first demonstration that dipolar forces alone can create an orientationally ordered liquid state. It is also the first time that the existence of a ferroelectric nematic phase has been established for a model liquid. This discovery solved a long standing problem in theoretical physics, and created a new direction in search for new liquid crystal materials(Phys. Rev. Lett. paper( 68, 2043, 1992), cited about 180 times). In recent years, Prof. Wei developed tools of molecular simulation and applied them to study biological systems with relevance to computed aided drug design and structural biology. With more than 100 journal papers and SCI 1800 citations, he is becoming a leading figure in the area of structural bioinformatics. Prof. Wei organized a few important international conferences recently, for example, International Conference on Computational and System Biology, Oct. 9-11, 2009, Shanghai , China , Theory and Application of Computational Chemistry, Sept. 23-27, 2008, Shanghai , China , 2 nd IEEE Conferences on Bioinformatics and Biomedical Engineering, May 16-20, 2008, Shanghai , China .