Post on 13-Jan-2016
description
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 JianjianSubject: Pharmaceutical chemistry
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Experimental plan
Topic schedule implementation scheme
References5
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Outline
1 Introduction to research topics
2
2 Current research situation at home and abroad
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
MethodMethod ObjectiveObjective
Contents
Contents
Structural change responsible for the drug resistance
Energetic changes responsible for drug resistance
Research method and objective
Description of the contents Description of the contents
Using the molecular dynamics simulations,when the complex isstable, calculate the binding free energy analyse the xianghuzuo Yong between the protease and the inhibitor
1 Introduction to my research
2)May be critical for the development of novel inhibitors that are less susceptible to drug
resistance.
Significance of the topic
1)provide some insights into the resistance mechanism of NS3/4A protease mutants to
BI201335
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 deacetylase-like 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
Research contents
Step three
Content analysis
Step one
Preparation of initial
structures
Step four
Results and conclusions
Step two
Molecular dynamics simulations
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.
Do molecular dynamics using the Amber10.0 software package
.
The general Amber force field (GAFF) used to generated the small molecular parameters
Prepare the inhibitors parameters with Antechamber module of Amber10 package..
The standard AMBER force field (ff99SB) will be used to decribe the protein parameters
0101
0303
02020404
Do molecular dynamics using the Amber10.0
software package
Molecular dynamics simulations
Content analysis
Dynamics
stability
Root-mean square Deviation (RMSD)
MM-PBSA approach
Binding free energy
Hbond and distance
Ptraj script
Decompose the
total binding energy to each residue.
Decompose energy
Results and conclusions
Text in here Text in here
2005 2008
The resistance mechanism
4 Topic schedule
2012 2013
90% 96%
35%70%
Month 3-Month 6Literature researchData reduction
Month 12–Month 3The first draft of a paper
2012
Month 11- Month 3literature reviewopening speechopening speech
Month 8-Month 11theoretical researchConstruct paperbasic framework
Month 4-Month 5final manuscriptsPrint Finisherprepare for the speech
2011 First half of 2012 Latter half of 2012 2014
2012 2014
5 References• [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 deacetylase-
like protein:Binding hydroxamic acid inhibitors.Proteins.2009,73(1):134-147.
Thank You!