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Samira H. Alamudi Usman Sumo Friend Tambunan

DESIGNING CYCLIC PEPTIDE INHIBITOR OF DENGUE VIRUS NS3-NS2B PROTEASE BY USING MOLECULAR DOCKING APPROACH. Samira H. Alamudi Usman Sumo Friend Tambunan. Department of Chemistry, Faculty of Mathematics and Natural Sciences, University of Indonesia. Introduction.

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Samira H. Alamudi Usman Sumo Friend Tambunan

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  1. DESIGNING CYCLIC PEPTIDE INHIBITOR OF DENGUE VIRUS NS3-NS2B PROTEASE BY USING MOLECULAR DOCKING APPROACH Samira H. Alamudi Usman Sumo Friend Tambunan Department of Chemistry, Faculty of Mathematics and Natural Sciences, University of Indonesia

  2. Introduction Diseases caused by dengue virus infections emerged as endemic in tropical and subtropical region. Dengue infections place some 2.5 billion people (or 40% of the world population) at risk and are significant cause of mortality and currently estimated to infect 50-100 million people globally per year (www.who.intr/). http://gamapserver.who.int/mapLibrary/ 08/09/2009 USF-SHA

  3. DEN1 Dengue virus DEN3 DEN2 DEN4 Introduction Dengue virus mostly transmitted by Aedes aegypti. Clinical illness of dengue infection: • Dengue fever (DF) • Dengue hemorrhagic fever (DHF) • Dengue shock syndrome (DSS) Dengue virus has four antigenically distinct serotypes, but genetically closely related to one another (S.N., Bennett, et al., 2006) 08/09/2009 USF-SHA

  4. Introduction Until today, no vaccine or anti-dengue viral drug currently available in the market. To search potential peptide inhibitor for dengue’s vital enzyme AIM NS3 protein  serine protease 08/09/2009 USF-SHA

  5. Dengue Virus • - RNA (+) - genus Flavivirus - family Flaviviridae Consist of 10,723 nucleotides and encodes a single polyprotein precursor of 3,391 amino acid. Melino, Sonia. et al., 2007 08/09/2009 USF-SHA

  6. Life Cycle x Karin dan Franz, 2006 08/09/2009 USF-SHA

  7. Enzyme structure (retrieved from the Protein Data Bank, accession code 2FOM) Binding site and substrate analysis Peptides amino acid sequence determination Ligands (peptides) structure building Enzyme and ligands structure optimization Molecular docking Docking Analysis Methods 08/09/2009 USF-SHA

  8. Result and Disscusion Cyclopentapeptides: Control/standard: Bz-Nle-K-R-R-H, Ki = 5.8 μM (Z. Yin, et al.,2006) 08/09/2009 USF-SHA

  9. Result and Disscusion All the ligands are superimposed at the catalytic site. The catalytic triads are labeled as His51, Asp75, and Ser135 and are shown as balls and sticks 08/09/2009 USF-SHA

  10. Estimated free energies of binding for all the ligands are lower than the standard. This may be attributable to the lower number of torsions found in ligands, hence lowering torsional free energies. And also because of stable complex enzyme-ligand formation (negative free energy) Ki values are reasonably small, indicating the formation of stable enzyme- ligand complex. Result and Disscusion Docking result 08/09/2009 USF-SHA

  11. Result and Disscusion Hydrogen bond 08/09/2009 USF-SHA

  12. Asp75 His51 Ser135 Asp75 His51 Ser135 (b) Result and Disscusion Contact Residue 08/09/2009 USF-SHA

  13. Result and Disscusion Enzyme-ligand complex conformation 08/09/2009 USF-SHA

  14. Asp75 (b) His51 Ser135 (a) Result and Disscusion 08/09/2009 USF-SHA

  15. Conclusions • There are seven cyclopentapeptides inhibitor designed in this study: CKRRC, CGRRC, CRGRC, CRTRC, CTRRC, CKRKC and CRRKC. • The free energy binding and estimated Ki values for all the ligands are considerably small (within micromolar range), indicating that the molecules bind considerably well to the binding sites. • Molecular docking in this study shown that cyclopentapeptide CKRKC is the best peptide inhibitor candidate whose the value of its free energy binding -8.39 kcal/moland estimated inhibition constantKi 0.707 μM. • Cyclopentapeptide CKRKC could be proposed as a potential inhibitor to the serine protease activities of DEN2 dengue virus. 08/09/2009 USF-SHA

  16. Thank You…. 08/09/2009 USF-SHA

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