Structure Bioinformatics, TCM Databases, and Personalized ... - KIAS

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Oct 1, 2013 (3 years and 10 months ago)

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Structure Bioinformatics, TCM Databases, and Personalized Drug
Design


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 Cen
ter, Key Lab of Systems Biology, Shanghai Institutes for Biological
Science, Chinese Academy of Science, Shanghai 200031, China


Abstract



Structure bioinformatics tools have been developed to generate 3D structure from
sequences of novel genes[1
-
3]. It a
llows 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 t
hat 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 conditi
on 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.
In or
der to gain
insight for developing personalized drugs, the three dimensional structure of
CYP2C19 and its two SNPs, W120R and I331V, have been developed based on the
crystal structure of CYP2C9 (PDB code 1R9O), and their structure
-
activity
relationship wit
h the ligands of CEC, Fluvoxamine, Lescol, and Ticlopidine
investigated through the structure
-
activity relationship approaches. By means of a
series of molecular docking experiments, the binding pockets of CYP2C19 and its
two SNPs for the four compounds ar
e explicitly defined that will be useful for
conducing mutagenesis studies, providing insights into personalization of drug
treatments and stimulating novel strategies for finding desired personalized drugs



References

1.

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).

2.

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).

3.

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

4.

Jing
-
fang Wang, Dong
-
Qing Wei*, Kuo
-
chen Chou
*
, “Drug Candidates From
The Traditional Chinese Medicine”, Current Topics Med. Chem,
8
,
1
56
-
1665
(2008).



5.

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

6.

Jing
-
Fang Wang , Dong
-
Qing Wei*, Kuo
-
Chen Chou, “Pharmacogenomics and
Personalized Use of Drugs”, Current Topics in Medicinal Chemistry,
8
,
1573
-
1579(2
008).

7.

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 t
ext book for Harvard and MIT students
.