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FRAGMENT- BASED DRUG DESIGN. Yemane Mengistu Michigan State University January 30, 2008. Annual Research and Development Expense. 160. 120. Annual NME Approvals. Expense ($ Billions). 80. 40. R & D Investment. Source : Pharma, FDA, Lehman :. NME ( New Medical Entities ).

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FRAGMENT- BASED DRUG DESIGN


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    1. FRAGMENT- BASED DRUG DESIGN Yemane MengistuMichigan State UniversityJanuary 30, 2008

    2. Annual Research and Development Expense 160 120 Annual NME Approvals Expense ($ Billions) 80 40 R & D Investment Source : Pharma, FDA, Lehman : NME ( New Medical Entities )

    3. Drug Discovery Process Combinatorial Chemistry Natural products High-throughput Screening (HTS) • Target molecule • eg. Enzymes Toxicity Clinical trials Lead & Drug optimization

    4. Creating a Library A Natural Product Thymidinyl nucleoside Sun, D., Lee, R.E. Tetrahedron Lett. 2005, 46, 8497-8501

    5. Creating a Library Using Ugi Chemistry Thymidinyl nucleoside library

    6. Creating a Library Using Ugi Chemistry Walters, W.P., Stahl, M.T., Murcko, M.A. Drug Discovery Today1998, 3,160-178

    7. Creating a Thymidinyl Ugi Library Sun, D., Lee, R.E. Tetrahedron Lett. 2005, 46, 8497-8501

    8. Thymidinyl Ugi Library Sun, D.; Lee, R.E. Tetrahedron Lett. 2005, 46, 8497-8501

    9. High-throughput Screening (HTS) • A process of assaying a large number of compounds against biological targets. • Up to 100,000 compounds can be analyzed in a day. • Robots can usually prepare and analyze many plates simultaneously. http://www.metprog.org.uk/images/manufacturing_icon.jpg

    10. What types of compounds become leads from an HTS?

    11. Lipinski’s Rules (Pfizer) HTS Drug like (Rule of 5) Lead-likeness Molecular weight ~300 ≤ Molecular weight 500 # Hydrogen Bond acceptors 10 ≤ Fewer Hydrogen Bond Acceptors Sum of N and O Sum of N and O ≤ 5 # Hydrogen Bond Donors Sum of NH and OH Lipophilicity ClogP<5 Lipophilicity ClogP<3 Low to high affinity for the target receptor Drug like behavior Lead like behavior Congreve, M. et al. Drug Disco. Today.2003,8, 876-877 Lipinski, C.A. et al. Adv.Drug Deli.Rev.1997,23,3-25.

    12. 1µM 10 nM 1mM 600 Drug Candidates HTS hits Drugs 500 Lead optimization 400 Relative Molecular Mass 300 200 HTS Library 100 0 Potency

    13. A Typical Drug Discovery Cascade HTS 1,000,000 HTS Hits 2000 Hits actives 1200 Increased risk of failure Lead series 50-200 Drug candidates 10 Drug 1 Opera ,T.I. J Comput. Aided Mol Des2002, 16, 323-334

    14. HTS GlaxoSmithKline’s HTS Scoreboard Chemical engineering news, 2004, 82 ,23-32

    15. Fragnomics: Fragment Based Drug Design • An approach that uses small and relatively simple molecules to make lead compounds Potential Medicinal compounds Look for affinity Lead Fragments Target Merge and Expand ~Enzymes, etc

    16. HTS hits Drug Candidates Drugs Lead optimization Fragments 1µM 10 nM 1mM MW of Average HTS Hits and Fragments 600 500 400 300 Relative Molecular Mass 200 100 0 Rees D.C, Congreve M, Murray C.W, Carr R .Nat. Rev. Drug Discov. 2004, 3:660 Potency

    17. Fragnomics: Fragment Based Drug Design Conventional HTS approach Fragment based drug design Kd>100µM • Erlason D.A, McDowell RS, O’Brien T. J Med Chem.2004, 47:3463-82 • Lewis, W.G.et al Angew. Chem. Int. Ed. Engl. 2002, 41,1053-1057

    18. Fragnomics: Fragment Based Drug Design Conventional HTS approach Fragment based drug design Swayze, E.E, et al.J.Med.Chem. 2003, 46, 4232-4235

    19. What Qualifies Compounds to be Fragments? • Molecular Weight Mr ~300 Da • H-bond donors (HBD) <3 • H-bond acceptors (HBA) <3 Congreve, M. et al. Drug Discov.Today2003,8, 876-877

    20. What Qualifies Compounds to be Fragments? Molecular Weight Mr ~300 Da H-bond donors (HBD) <3 H-bond acceptors (HBA) <3 Fragment IC50 = 1.3mM Mr =200 HBD= 2 HBA=3 Lead for protein kinase inhibitor IC50 = 65 nM Mr =456 Congreve, M. et al. Drug Discov.Today2003,8, 876-877

    21. What Qualifies Compounds to be Fragments? • Clog P <3 • A measure of Lipophilicity of a compound • Polar Surface Area (PSA) <60 • A measure of permeability through the cell membrane. Fragment Lead for protein kinase inhibitor Clog P=1.92 PSA=48.14 Clog P=3.07 PSA= 77.6 Congreve, M. et al. Drug Discov.Today2003,8, 876-877 Ertl, P.et. al. J.Med.Chem. 2000, 43,3714-3717

    22. Some Common Drug-Based Fragments Ring system from drug Heterocyclic system Side chains Hartshorn, M.J., Murray, C.W.et.al. J. Med. Chem. 2005, 48, 403-413

    23. Conventional HTS vs. Fragonomics Based on Central Scaffold 100 X R1 100 X R2, and 100 X R3 yields 100 100 100 A library with 1 million compounds Variations yield a library of only 300 compounds Carr, R, and Hann, M. Modern Drug Discov. 2002, 45-48

    24. Conventional (HTS) Drug Design Erlanson, D.A, Hansen, K.S. Curr Opin Chem Biol. 2004, 8,399-406.

    25. Conventional (HTS) and Fragment Based Drug Design Erlanson, D.A, Hansen, K.S. Curr Opin Chem Biol. 2004, 8,399-406.

    26. Fragment Based Drug Design 1. Prepare set of potential binding elements with a common chemical linkage group Maly, D.J., Choong, D.J., and Ellman, J.A. Proc.Natl.Acad.Sci.USA. 2000,97,2419-2424

    27. Fragment Based Drug Design 1. Prepare set of potential binding elements with a common chemical linkage group 2.Screen Potential binding elements Maly, D.J., Choong, D.J., and Ellman, J.A. Proc.Natl.Acad.Sci.USA. 2000,97,2419-2424

    28. Fragment Based Drug Design 1. Prepare set of potential binding elements with a common chemical linkage group 2.Screen Potential binding elements 3. Prepare library of all possible combinations of linked binding elements. Maly, D.J., Choong, D.J., and Ellman, J.A. Proc.Natl.Acad.Sci.USA. 2000,97,2419-2424

    29. Fragment Based Drug Design 1. Prepare set of potential binding elements with a common chemical linkage group 2.Screen Potential binding elements 3. Prepare library of all possible combinations of linked binding elements. 4.Screen library of linked binding elements Maly, D.J., Choong, D.J., and Ellman, J.A. Proc.Natl.Acad.Sci.USA. 2000,97,2419-2424

    30. Application of Fragment based drug design 1. Protein kinase inhibitors • Tyrosine kinase (Src) activate numerous signaling pathways within cells, leading to cell proliferation, differentiation , migration and metabolic changes • Src kinases have been implicated in the pathology of tumors, osteoclast-mediated Bone resorption and disorders associated with T-cell proliferation Scapin,G. Drug Discovery today. 2002, 7,2002 Maly, D.J., Choong, D.J., and Ellman, J.A. Proc.Natl.Acad.Sci.USA. 2000,97,2419-2424

    31. Library for the Protein kinase inhibitor D.J.Maly, I.C.Choong and J.A, Ellman,Proc.Natl.Acad.Sci.USA,2000,97,2419-2424

    32. Library for the Protein kinase inhibitor Ki =41µM D.J.Maly, I.C.Choong and J.A, Ellman,Proc.Natl.Acad.Sci.USA,2000,97,2419-2424

    33. Library of protein kinase inhibitor D.J.Maly, I.C.Choong and J.A, Ellman,Proc.Natl.Acad.Sci.USA,2000,97,2419-2424

    34. Fragment-Based Design : Protein Kinase Inhibition 7 16 D.J.Maly, I.C.Choong and J.A, Ellman,Proc.Natl.Acad.Sci.USA,2000,97,2419-2424

    35. Correlation of linker structure with IC50 values for c-Src Inhibition

    36. Application of Fragment Based Drug Design 2. Matrix Metalloproteinase inhibitors • Matrix Metalloproteinases is a family of zinc-dependent endopeptidases. • Implicated in a variety of diseases including arthritis and tumor metastasis. • Conventional high-throughput screening failed to get non-peptide inhibitor. Haiduk, P.J. et al. JACS. 1997,119, 5818-5827

    37. Application of Fragment Based Drug Design 2. Matrix Metalloproteinase Inhibitors Kd=17 mM Kd=0.2 mM IC50=57 nM Haiduk, P.J. et al. JACS. 1997,119, 5818-5827 Puerta, D.T, Lewis J.A. JACS. 2004, 126, 8389

    38. Application of Fragment Based Drug Design 2Matrix Metalloproteinase Inhibitors IC 50 = 0.5 nM ABT-518 , a drug candidate in clinical trial by Abbot Pharmaceutical Company Wada, C.K, et al. J.Med.Chem. 2002, 45, 219-232

    39. Application of Fragment Based Drug Design 3. Thymidylate synthase (TS) • Is the sole source for production of thymidine monophosphate (dTMP). • dTMP plays a central role in DNA synthesis . • It has been a target for dividing cancer cells. Banerjee D, Mayer-Kuckuk P, Capiaux G, et al.Biochim. Biophys. Acta, 2002, 1587,:164-73.

    40. Application of Fragment based Drug Design Site Directed Ligand Discovery for TS TS Screen against library of Disulfide-containing small Molecules Erlanson, D.A, Braisted, A.C .Proc.Natl.Acad.Sci.USA. 2000, 97 ,9367–9372

    41. Preparation of Disulfide-Containing Library Members Parlow, J.J. & Normansell, J.E.Mol.Diversity 1995,1, 266-269

    42. Synthesis of Sulfonyl Libraries Erlanson, D.A, Braisted, A.C .Proc.Natl.Acad.Sci.USA. 2000, 97 ,9367–9372

    43. Thymidylate Synthase Inhibitor Selected Non selected Erlanson, D.A, Braisted, A.C .Proc.Natl.Acad.Sci.USA. 2000, 97 ,9367–9372

    44. Erlanson, D.A, Braisted, A.C .Proc.Natl.Acad.Sci.USA. 2000, 97, 9367–9372

    45. Thymidylate Synthase Inhibitor Erlanson, D.A, Braisted, A.C .Proc.Natl.Acad.Sci.USA. 2000, 97 ,9367–9372

    46. Application of Fragment Based Drug Design 4. Cysteine Aspartyl Protease-3 ( Caspase-3) • Mediator of apoptosis ( programmed cell death). • They are responsible for the cleavage of the key cellular proteins such as cytoskeleton proteins. • Reducing the apoptotic response in diseases with dysregulated apoptosis such as myocardial infarction, stroke, traumatic brain, Alzheimer’s disease, and Parkinson diseases could benefit . Hotchkiss, R.S. et al. Nat. Immunol. 2000, 1 , 496-501

    47. Tethering with Extenders-dynamically Assembling Fragments Caspase-3 using extender A Caspase-3 using extender B Erlanson, D.A, Hansen, K.S. Curr Opin Chem Biol. 2004, 8,399-406.

    48. Assembly of the Extender with Enzyme and with Fragment Library

    49. Assembly of the Extender with Enzyme and with Fragment Library A B c Erlanson, D.A, Lam, J.W, Wesmann ,C. Nat. Biotechnol. 2003, 21, 308-314