Download Molecular modeling study on the resistance mechanism of HCV NS3

Molecular modeling study on the resistance mechanism
of HCV NS3/4A serine protease mutants to BI201335
Supervisor: Richard Hsung Professor ,
Dr. Wei Jing
Student: Fu Jianjian
Subject: Pharmaceutical chemistry
Outline
Introduction to research topics
1
12
Current
home and abroad
Clickresearch
to addsituation
title inathere
2
3
4
5
Experimental plan
Topic schedule implementation scheme
References
1 Introduction to my research
•
HCV is a serious and growing threat to human health
– HCV NS3/4A serine protease is a trypsin-like protease essential
for RNA replication.
--- Drug resistance of HCV NS3/4A protease often occurs to its
inhibitors.
– BI201335 , a competitive inhibitor contains a unique C-terminal
carboxylic acid that binds noncovalently to the active site is in
phase3 of clinical trials,which is devoleped by Boehringer
Ingelheim incoportion
– To data,there have not any report to the drug resistant
mechanism research to BI201335
1 Introduction to my research
Research method and objective
Method
Using the molecular
dynamics simulations,
when the complex is
stable, calculate the
binding free energy
analyse the xianghuzuo
Yong between the
protease and the
inhibitor
Description of the contents
Objective
Contents
Structural change responsible
for the drug resistance
Contents
Energetic changes responsible
for drug resistance
Description of the contents
1 Introduction to my research
1)provide some insights
into the resistance mechanism
of NS3/4A protease mutants to
BI201335
Significance of
the topic
2)May be critical for the
development of novel inhibitors
that are less susceptible to drug
resistance.
2 Current research situation at home and abroad
The molecular dynamics is widely used to evaluate the
drug resistance mechanism in HIV drugs and anti-cancer
drugs.
1 Chunli Yan,Comparative molecular dynamics simulations of histone deacetylaselike protein:Binding hydroxamic acid inhibitors.Proteins.2009,73(1):134-147.
2 GU HUI et al.Molecular dynamics simulations exploring drug resistance in HIV-1
protease.Bioinformatics.2010,55(24):2677-2683.
3 Yufeng Cai et al.Differential Flap Dynamics in Wild-Type and a Drug Resistant
Variant of HIV-1 Protease Revealed by Molecular Dynamics and NMR Relaxation. J.
Chem. Theory Comput., 2012, 8 (10): 3452–3462.
3 Experimental plan
Step one
Step two
Preparation of initial
Molecular dynamics
simulations
structures
Research
contents
Step three
Step four
Content analysis
Results and
conclusions
Preparation of initial structures
1 Download the X-ray crystal structure of wild-type HCV
NS3/4A protease complexed with BI201335
2 MOE software will be applied to generate the 3D structure of
the studies mutants (eghit complexes including the wild type
one) in complex with BI201335 by substituting specific residues
using the wide type model as the template.
Molecular dynamics simulations
Do molecular dynamics using
the Amber10.0 software package
.
04
01
Do molecular
dynamics using
the Amber10.0
software package
The general Amber force field
(GAFF) used to generated the
small molecular parameters
03
Prepare the inhibitors
parameters with Antechamber
module of Amber10 package..
02
The standard AMBER force
field (ff99SB) will be used to
decribe the protein parameters
Content analysis
Root-mean
square
Deviation
(RMSD)
Dynamics
stability
MM-PBSA
approach
Ptraj script
Binding free
energy
Hbond and
distance
Decompose the
total binding
energy to each
residue.
Decompose
energy
Results and conclusions
Text in here
Text in here
The resistance mechanism
2005
2008
4 Topic schedule
2012
2013
Month 12–Month 3
Month 3-Month 6
Literature research The first draft
Data reduction
of a paper
90%
2011
2012
First half of 2012
2012
96%
Latter half of 201270%2014
35%
2014
Month 11- Month 3 Month 8-Month 11th Month 4-Month 5
literature review eoretical research final manuscripts
opening speech
Construct paper
Print Finisher
basic framework
prepare for the s
peech
5 References
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[1] Diane Thibeault at el. Sensitivity of NS3 Serine Proteases from Hepatitis C Virus
Genotypes 2 and 3 to the Inhibitor BILN 2061. JOURNAL OF VIROLOGY,2004,78(14)
:7352–7359
[2] Christopher T. Lemke et al.Combined X-ray, NMR, and Kinetic Analyses Reveal
Uncommon Binding Characteristics of the Hepatitis C Virus NS3-NS4A Protease
Inhibitor BI 201335. The journal of biological CHEMISTRY,2011,286(13):11434 –
11443.
[3] Paul Y. Kwo.Boceprevir: a novel nonstructural 3 (NS3) protease inhibitor for the
treatment of chronic hepatitis C infection. Therapeutic Advances in Gastroenterology.
(2012) 5(3) 179 –188.
[4] Jean-Michel Pawlotsky.Therapeutic implications of hepatitis C virus resistance
to antiviral drugs. Therapeutic Advances in Gastroenterology. (2009) 2(4) 205–219.
[5] Paul Y. Kwo.Boceprevir: a novel nonstructural 3 (NS3) protease inhibitor for the
treatment of chronic hepatitis C infection. Therapeutic Advances in Gastroenterology.
(2012) 5(3) 179 –188.
[6] Chunli Yan,Comparative molecular dynamics simulations of histone deacetylaselike protein:Binding hydroxamic acid inhibitors.Proteins.2009,73(1):134-147.
Thank You!