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Microtubules in 5 minutes

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Microtubules in 5 minutes

  1. 1. Jack Tuszynski Cross Cancer Institute Edmonton, AlbertaMathematical Modelling and Pharmaceutical Development
  2. 2. *Rebuilding a Research Team* Torin Huzil, PhD Vahid Rezania, PhD Avner Priel, PhD-Israel Przemek Chelminiak, PhD-UK Linda Payet, PhD Rebeccah Marsh, M.Sc.-US Eric Carpenter, B.Sc. Melissa Gajewski, BSc Evan Kelly, BSc Travis Craddock, BSc Tyler Luchko, B.Sc. Hon. Kristy Beinert, student Joseph Hajduk, student
  3. 3. Standard Cancer Treatment Modalities: Radiation therapy Chemotherapy Surgery Gene Therapy
  4. 4. Our Premise:computational modeling of cancer processesand treatments can help find newchemotherapy compounds and guide clinicaldelivery of treatments to improve cure rates
  5. 5. Key Objectives: Develop large-scale computational modeling ofcancer processes and treatments Find effective chemotherapy compounds (new andrepurposed) and modalities of their clinical delivery toimprove cure rates Experiment with novel techniques of attackingcancer cells
  6. 6. Microtubules and CancerOne of the critical components of cell division are the microtubules. We selectively target microtubules, disrupting cell division, thereby killing dividing cells.The presence of severalhuman tubulin isoformsprovides us with a uniqueplatform on which todevelop drugs that haveincreased specificities forthose expressed incancerous cells.
  7. 7. Understanding Microtubules
  8. 8. Microtubules
  9. 9. Zeroing in on the target
  10. 10. Simulating Microtubules
  11. 11. Tubulin Structure basic unit is dimer, two protein chains each chain is linked amino acids chain has compact, folded form backbone shows chain structure
  12. 12. Protein Backbone StructureTwo common forms• α-helix helical backbone• β-sheet straight, parallel backbone sections
  13. 13. Different Sequences— Different Properties sequences differ in shape • chemistry • movement tubulins differ • human isotypes • between species
  14. 14. Spatial Fitting of DrugsUtilizes the visualinspection of a Targetbinding site within atarget, followed bythe modification of adrug to producebetter binding to thetarget.
  15. 15. Binding pockets for colchicine and taxanes docetaxel colchicine paclitaxel
  16. 16. Paclitaxel from the Pacific Yew
  17. 17. Colchicine from Autumn Crocus
  18. 18. Vinca alkaloids from periwinkle
  19. 19. Known tubulin inhibitors are not isotype specific -hence side effects…but:“Conceivably, if one knew the tubulin isotype and microtubule regulatory protein composition of a specific tumor cell, one could design or choose drugs to selectively target that tumor”Jordan and Wilson, Nature Reviews Cancer, 2004
  20. 20. Tubulin Amino Acids Involved in Colchicine Binding class I EPYNATLSVH QLVENTDETYCIDNEALYDICFRTLKLTTPTY G DLNHLVSATM S G VTTCL 240 class II EPYNATLSVH HLVENTDETYSIDNEALYDICFRTLKLTTPTY G DLNHLVSATM S G VTTCL 240 class II I EPYNATLSIHQLVENTDETYCIDNEALYDICFRTLKLATPTY G DLNHLVSATM S G VTTSL 240 class VI EPYNAVLSIHQLIENAD A CFCIDNEALYDICFRTLKLTTPTY G DLN HLVSLTM S GITTSL 240 * * * * : : : * * :* * * * * * * * * * * * * * * * : * * * *.****: .* * * * * * *.* * * * * * :**. class I RFPG Q LNA DLRKLAV N M VPFPRLHFF MP GFAPLTSRG S Q Q Y R ALTVPELTQ Q VFDA K N M M 300 class II RFPG Q LNA DLRKLAV N M VPFPRLHFF MP GFAPLTSRG S Q Q Y R ALTVPELTQ Q M F D SK N M M 300class II I RFPG Q LNA DLRKLAVN M VPFPRLHFF MP GFAPLTARG S Q Q Y R ALTVPELTQ Q MF D A K N M M 300class VI RFPGQL N A DLR KLAVNM V PFPRLHFF MPGF APLTA Q G S Q Q YR ALSVAELT Q Q M F D A R N T M 300 * * * * * * * * * * * * * * . * * : * * *.:. * * : *: * * * * * * * * * * * * * * ** * * : * * ** ** * * * : *class I AACDPR H G RYLTVA AVFRG R M S M K EVDE Q M LNV Q N K NSSYFVEWIPN NV K TAVC DIPPR G 360class II AACDPR H G RYLTVA AIFRG R M S M K EVDE Q M LNV Q N K NSSYFVEWIPN NV K TAVC DIPPR G 360 class II I AACDPR H G RYLTVATVFRG R M S M K EVDE Q M LAIQSK N SSYFVEWIPN NV K VAVC DIPPR G 360 class VI AACDLRR G RYLTVACIFR G K M STKEVD Q Q LLSV QTRNSSCFVEWIPNNVKVAVC DIPPR G 360 * * * * * * *: * * : * : : : : * *: : * * . * * * * * : * . * * . * * * : * * * .* * * * * * * *
  21. 21. The Colchicine Binding Site: βII and βIII Tubulin βII βIIIThr 353 Cys 239 Val 353 Ser 239 Tyr 200 Arg 200
  22. 22. Colchicine Bound toβII and βIII TubulinβII βIII
  23. 23. Colchicine Derivatives that may Differentiate Isoforms6 membered extendedaromatic ring methyl 5 membered extended ring hydroxyl
  24. 24. Colchicine Derivatives Bound to Tubulin Isoforms βII βIII Void
  25. 25. Quantum Mechanical MethodA method that is applicable for calculating atomic and molecularproperties of any system without the need for parameterizationAn approach that describes the dynamic distribution of electrons inthe systemCan calculate molecular geometries, transition states, spectra, etc.A powerful method for predicting stability of molecules andenergetics of chemical reactions
  26. 26. Quantum Mechanical Optimization (An example)Before After
  27. 27. Comparison of Molecular Mechanics and Quantum Mechanical Approach for Molecular DynamicsClassical MD Quantum Mechanical MD• Simplified description of the atomic • Atomic / molecular interactions are configurations and interactions in calculated directly from first principles the system• Forces acting on the system are defined • Forces acting on the system are directly using fixed sets of parameters (i.e. force calculated fields)• Computationally fast: • Computationally expensive: thousand-million atoms < 500 atoms• Dynamic distribution of electrons in the • Dynamic distribution of electrons in the system is NOT described system is described• Difficult to model chemical bond • Easily handles bond making / bond making / bond breaking processes breaking
  28. 28. Hybrid QM/MM MD simulation QM MMCoupling of QM and MM modeling QM - an active site; a reaction center; Tubulin-colchicine solute MM - enzyme structure; explicit solvent
  29. 29. Our strategy:Exquisite design of drugs for patient-specificprotein expression using clues from MotherNatureChemical SynthesisIn Vitro and In Vivo TestingFurther Improvement and Refinement
  30. 30. Our other projects:Ultrasound resonanceElectroporationMagnetic field guided drug deliveryLaser-induced activation of conjugatedcompoundsMicrotubule hybridizationTaxane pharmacokinetics

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