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Given an oral presentation "ANALOGUE BASED DESIGN OF AURORA-B INHIBITORS" in the National Conference on Biotechnology and Bio-informatics-2006

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  1. 1. ANALOGUE BASED DESIGN OF AURORA-B INHIBITORS Dr. Sarma Jagarlapudi Dr. B. Syama Sundar Head of Informatics Dept. of Chemistry GVK Biosciences Acharya Nagarjuna University Hyderabad Guntur Jayashankar. L
  2. 2. Aurora Kinase Inhibitor (AKI) as Anticancer agents <ul><li>25 million people living with cancer today/  to around 30 million people by 2020.. </li></ul><ul><li>Aurora Kinases A B and C are new key targets (proved during 2004). e </li></ul><ul><li>Distruption of mitosis which leads arrest of cell proliferation </li></ul><ul><li>Scaffolds (indolinone, quinozoline, pyrazole & pyrimidine derivatives) </li></ul>
  3. 3. AURORA KINASE <ul><li>Serine/threonine kinase </li></ul><ul><li>Frequently overexpressed Aurora kinase is overexpressed in many tumors and has been shown to lead to malignant transformation and aneuploidy </li></ul><ul><li>AKI disrupts mitosis and cellular division in tumor cells and promote premature exit from mitosis enhancing rate of cell death </li></ul>
  4. 4. CLASSIFICATION <ul><li>Aurora are of a. Aurora A, b. Aurora B & c. Aurora C </li></ul>
  5. 5. Mechanism
  6. 6. Roles of Aurora Kinases during Mitosis
  7. 7. <ul><li>a- Prophase </li></ul><ul><li>b- Prometaphase </li></ul><ul><li>c-metaphase </li></ul><ul><li>d-anaphase </li></ul><ul><li>e-telophase Aurora-A localizes to the centrosomes during prophase (a) and Aurora B localizes to the centrosomes during prometaphase and metaphase (b and c) </li></ul><ul><li>Whereas in later stages of mitosis AURORA A is at the spindle poles (c, d and e) and also extends up the spindle. </li></ul><ul><li>After anaphase (d), however, Aurora-B localizes to the spindle midzone, and finally accumulates at the midbody during telophase (e). </li></ul>
  8. 8. Mitosis distruption by AKI <ul><li>During metaphase chromosomes will align at equator of the cell </li></ul><ul><li>At anaphase the duplicated chromosome (Chromatids will move towards opposite end and will get seperated </li></ul><ul><li>( Drugs Fut 2004, 30(1) </li></ul>
  9. 9. Catalytic active site THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 277, No. 45, (8), 42419–42422, 2002
  10. 10. Aurora Inhibitor VX-680
  11. 11. Aurora inhibitors 1) Drugs Fut 2004, 30(1), 2) Bioorg Med Chem Lett. 2006 Mar 1;16(5):1320-3
  12. 12. 3D-QSAR on AURORA B inhibitors <ul><li>Cerius2 ( Silicon Graphics Octane2 R12000 computer running Irix 6.5.12 ) </li></ul><ul><li>Cerius2 is a leading modeling and simulation environment for UNIX workstations which has particular strength in Rational drug design and Structure-based drug design </li></ul><ul><li>MFA ( Molecular field analysis ) </li></ul><ul><li>RSA ( Receptor surface analysis) </li></ul>
  13. 13. Molecular Structure Generation <ul><li>Training set – 27 molecules and the remaining molecules as test test </li></ul><ul><li>Geometric Optimization </li></ul><ul><li>Drieding force field </li></ul><ul><li>smart minimizer </li></ul><ul><li>MOPAC with the AM1 method </li></ul>
  14. 14. <ul><li>Manually aligned based on the biological activities </li></ul><ul><li>Further refinement in the alignment was carried out by an RMS based automated approach </li></ul><ul><li>In MFA, molecules were aligned using CH3 and H+ probes for steric and electrostatic interactions respectively using default grid values of 2 A ˚ </li></ul>Molecule Alignment
  15. 15. <ul><li>Molecular Field analysis </li></ul><ul><li>Considered the probes CH3 and H+ </li></ul><ul><li>Receptor surface analysis </li></ul><ul><li>Considered receptor surface descriptors, expressed as 3d-field descriptors, were derived from the van der Waals and electrostatic interaction energies between the receptor surface and CH3 and H+ groups as probes </li></ul>MFA and RSA
  16. 16. Aurora B inhibitors with observed and calculated biological activities possessing thequinazoline as common scaffold
  17. 19. Results and Discussion <ul><li>The regression analysis on training set molecules produced a QSAR model ( MFA ) and is shown in eq Activity = 1.50437 -0.014886 *”H+/425” +0.013275 *”H+/236” -0.01349 * “H+/208” -0.019607 * “CH3/352” +0.045393 *”H+/352” </li></ul><ul><li>The QSAR model generated by RSA is represented as eq Activity = -0.711179 -105.584 *”ELE/2441” -165.178 *”ELE/1071” -11.2535 *”ELE/2691” -125.784 *”ELE/91” + 00.923963 * ”ELE/591” </li></ul>
  18. 20. Stereo view of rectangular molecular field surrounding aligned molecules. Some of the field descriptors, which are involved in the QSAR eq 1, are indicated. Correlation of MFA (0.954).
  19. 21. Stereo view of the receptor surface which represents the vitural active site. Some of the RSA descriptors that constitute the QSAR eq 2 are labeled. Correlation of RSA (0.949)
  20. 22. Statistical Parameters for MFA and RSA
  21. 23. CONCLUSION <ul><li>Model developed by MFA and RSA methods has an r2 value of 0.954 and 0.949 respectively </li></ul><ul><li>The equation identified for the Aurora B kinase can be used to evaluate how well the newly designed compounds shows its biological activity before undertaking any further study including synthesis. </li></ul><ul><li>This application may help in identifying or designing compounds for further biological evaluation and optimization </li></ul>
  22. 24. References 1. Nicola M. Heron,a, Malcolm Anderson, David P. Blowers et al , “SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors”, Bioorg. Med. Chem. Lett. 16 (2006) 1320–1323. 2. J. A. R. P. Sarma, G. Rambabu, K. Srikanth, D. Raveendra and M. Vithal, “Analogue Based Design of MMP-13 (Collagenase-3) Inhibitors”, Bioorg. Med. Chem. Lett. 12 (2002) 2689–2693. 3. Elizabeth A Harrington, David Bebbington, JeffMoore et al, “VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo ”, Nat Med 2004 10(3) 262-267 4. Emilie Montembault, Claude Prigent, “ Aurora kinases:Therapeutic potential”, Drugs of the Future 2005, 30(1) 5. Andrew Mortlock, Nicholas J. Keen, Frederic H. Jung et al., ”Progress in the Development of Selective Inhibitors of Aurora Kinases”, Curr Top Med Chem . 2005;5(2):199-213. 6. Jung FH, Pasquet G, Lambert-van der Brempt C et al., Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors” J Med Chem. 2006 Feb 9; 49(3) 955-70