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Supervisor: Richard Hsung Professor ,

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: P harmaceutical chemistry. Outline. 1. Introduction to research topics. 1. 2.

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Supervisor: Richard Hsung Professor ,

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  1. 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

  2. Outline 1 Introduction to research topics 1 2 Click to add title in here Current research situation at home and abroad 2 3 Experimental plan 4 Topic schedule implementation scheme 5 References

  3. 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

  4. 1 Introduction to my research Research method and objective Method Objective 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 Contents Structural change responsible for the drug resistance Contents Energetic changes responsible for drug resistance Description of the contents Description of the contents

  5. 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.

  6. 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.

  7. 3 Experimental plan Step one Step two Preparation of initial structures Molecular dynamics simulations Research contents Step three Step four Results and conclusions Content analysis

  8. 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.

  9. Molecular dynamics simulations Do molecular dynamics using the Amber10.0 software package . Prepare the inhibitors parameters with Antechamber module of Amber10 package.. 01 Do molecular dynamics using the Amber10.0 software package 04 02 The general Amber force field (GAFF) used to generated the small molecular parameters The standard AMBER force field (ff99SB) will be used to decribe the protein parameters 03

  10. Content analysis Dynamics stability Decompose the total binding energy to each residue. Root-mean square Deviation (RMSD) MM-PBSA approach Ptraj script Binding free energy Hbond and distance Decompose energy

  11. Results and conclusions Text in here Text in here The resistance mechanism 2005 2008

  12. 4 Topic schedule 2012 2013 Month 3-Month 6 Literature research Data reduction Month 12–Month 3 The first draft of a paper 90% 96% 2011 First half of 2012 Latter half of 2012 2014 70% 35% 2012 2012 2014 Month 11- Month 3literature review opening speech Month 8-Month 11theoretical research Construct paper basic framework Month 4-Month 5 final manuscripts Print Finisher prepare for the speech

  13. 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.

  14. Thank You!

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