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Biology Oriented Synthesis A New Approach to Drug Design

Biology Oriented Synthesis A New Approach to Drug Design. Ruoying Gong Department of Chemistry March 12, 2009. What Is A Drug?. Drug is any substance used in the treatment, prevention, or diagnosis of disease The earliest drugs were natural products

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Biology Oriented Synthesis A New Approach to Drug Design

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  1. Biology Oriented SynthesisA New Approach to Drug Design Ruoying Gong Department of Chemistry March 12, 2009

  2. What Is A Drug? • Drug is any substance used in the treatment, prevention, or diagnosis of disease • The earliest drugs were natural products • Currently, more drugs are synthesized or semi-synthesized Collins Essential English Dictionary 2nd Edition, HarperCollins Publishers, 2006

  3. Drug Discovery • Trial and error testing • Random screening • Rational drug design • Structural information of a drug receptor • Information of a ligand Twyman, R., The Human Genome, 2002 Greer, J., et. al. J Med Chem. 1994, 37, 1035–1054

  4. Genomics/Proteomics • Potential Ligand Class • Crystal Structure • Cloning/Protein Expression • Domain Architecture Prediction • Bioinformatics • High Throughput Screen Rational Drug Design Process • Modeling • Docking • X-ray crystallography • NMR spectroscopy 200,000 compound/week Breinbauer, R., et. al. Angew. Chem. Int. Ed. 2002, 41, 2878 - 2890

  5. Potential Ligand Class • Synthesize Library of Similar Compounds • Hits • Lead • Drug Rational Drug Design Process Structure-activity relationship Bioavailability Formulation Biological tests Pharmacological tests Clinical tests Breinbauer, R., et. al. Angew. Chem. Int. Ed. 2002, 41, 2878 - 2890

  6. Drawback of Rational Drug Design • Time consuming • Costly • Limited understanding of drug receptors • Labour intensive • Low hit rate generated

  7. New Approach to Drug Design • Novel approach • Biology oriented synthesis • Created by Waldmann group • Max Planck Institute, Germany

  8. Drug and Drug Receptor • Knowledge of 3D structure of protein can assist in the design of drug scaffold Protein Catalytic core Ligand binding site

  9. Protein Structure Petsko, G. A. et. Al. Protein Structure and Function New Science Press Ltd., 2004

  10. Protein 1 • Protein 3 Protein Classification • Protein 2 • Protein family Similar 3D structure, function, and primary structure

  11. Proteins In the Same Family • Similar mechanism • Similar primary structure • Similar 3D structure • Similar amino acid residues

  12. Process of Ligand Discovery Target Protein Model Protein

  13. Waldmann Approach • Compare proteins with their 3D structure • Use a natural inhibitor as guiding structure for compound library development

  14. Protein Domain and Fold • Protein Domain • Tertiary structure folded independently as functional units • Protein fold • Conformational arrangement of protein secondary structures into tertiary structure Alberts, B. et. al. The Shape and Structure of Proteins. New York and London: Garland Science, 2002

  15. Protein Structure Architecture • Proteins • (100,000 – 450,000) • Domains • (4,000 – 50,000) • Folds • (800 – 1,000) SCOP databank: Murzin, A. G., Brenner, S. E., J. Mol. Biol. 1995, 247, 536 - 540

  16. Superfold and Supersite • Superfold: highly populated folds • Supersite: common ligand binding sites within a superfold Alberts, B. et. al. The Shape and Structure of Proteins. New York and London: Garland Science, 2002

  17. Classification Comparison Protein Family • Similar primary structure • Similar ligand binding site Protein Fold • Not related to primary structure • Similar ligand binding site

  18. Biology Oriented Synthesis • Biology • Protein Structure Similarity Clustering (PSSC) • Chemistry • Compound library synthesized according to guiding structure of natural inhibitor Koch, M. A. et al Drug Discovery Today. 2005, 10, 471 - 483

  19. Grouping Proteins Together • Protein Structure Similarity Clustering (PSSC) • 3D similarity of ligand binding sites • Ignore the amino acid sequence identity

  20. Computation Tools Used • Structural Classification of Proteins (SCOP) • Dali/Fold Classification Based on Structure-Structure Alignment of Proteins (FSSP)Database • Combinatorial Extension (CE) superimposition algorithm

  21. Protein of Interest • 1 Protein Clustering Process • Structural Alignment • Dali/FSSP • 2 • Interesting cases • Sequence identity (SI) < 20% • 3 • Superimposition of Catalytic Cores • Root mean square deviation (RMSD) < 5Å • 4 Grishin, N.V., et al J. Struct. Biol. 2001, 134, 167 - 185

  22. 1.Protein of Interest - Cdc25A • Phosphatase family • Rhodanese fold • Catalytic site contains Cys-430, Glu-431 • Regulates progression of cell division • A potential antitumor drug target Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  23. 2.Structure Alignment • Cdc25A • AChE • 11βHSD1,2

  24. 3.Acetylcholinesterase (AChE) • α/β-hydrogenase family • α/β-hydrogenase fold • Catalytic site contains Ser-200 • Terminate synaptic transmission • Target protein in the treatment of myasthenia gravis, glaucoma, and Alzheimer’s disease Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  25. 4.Superimposition Cys-430 (Cdc25A) Ser-200 (AChE) Super-site Cdc25A AChE Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  26. 2.Structure Alignment • Cdc25A • AChE • 11βHSD1,2 • 11βHSD1,2

  27. 3. Isoenzymes 11βHSD1,2 • Tyrosine-dependent oxidoreductase family • Rossmann fold • Tyrosine residue located at catalytic site Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  28. 11βHSD1 • Reduces cortisone to the active hormone cortisol • Potential target for treatment of obesity, the metabolic syndrome, and type 2 diabetes Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  29. 11βHSD2 • Catalyzes the oxidation of cortisol into the inactive cortisone • Inhibition causes sodium retention resulting in hypertension Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  30. 4.Superimposition Super-site Cdc25A 11βHSD1 11βHSD2 Cys-430 (Cdc25A) Tyr-183 (11βHSD1) Tyr-232 (11βHSD2) Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  31. Structure Alignment • Cdc25A • AChE • 11βHSD1,2 • 11βHSD1,2

  32. Superimposition Cys-430 (Cdc25A) Tyr-183 (11βHSD1) Ser-200 (AChE) Super-site Cdc25A 11βHSD1 AChE Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  33. Cluster Member Comparison

  34. Compound Library Discovery

  35. Dysidiolide: Natural Inhibitor of Cdc25A Dysidiolide, IC50=9.4μM Natural inhibitor of Cdc25A γ-hydroxybutenolide Brohm, D., et. al. Angew. Chem. Int. Ed. 2002, 41, 307 - 311

  36. Dysidiolide: Natural Inhibitor of Cdc25A γ-hydroxybutenolide α,β-Unsaturated lactone Brohm, D., et. al. Angew. Chem. Int. Ed. 2002, 41, 307 - 311

  37. Representative Synthesis

  38. γ-Hydroxybutenolides Synthesis Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  39. α,β-Unsaturated Lactones Synthesis Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  40. Results • 147 compounds synthesized • Contains γ-hydroxybutenolide or α,β-unsaturated lactone • Inhibitors with these structures have never been reported

  41. Best Compounds Natural inhibitor of Cdc25A Dysidiolide, IC50=9.4μM Cdc25A, IC50=0.35μM AChE, IC50>20μM 11βHSD1, IC50=14μM 11βHSD2, IC50=2.4μM Cdc25A, IC50=45μM AChE, IC50>20μM 11βHSD1, IC50=10μM 11βHSD2, IC50=95μM Cdc25A, IC50=1.8μM AChE, IC50>20μM 11βHSD1, IC50=19μM 11βHSD2, IC50=11μM Cdc25A, IC50>100μM AChE, IC50>20μM 11βHSD1, IC50=19μM 11βHSD2, IC50=5.3μM Koch, M. A., Wittenberg, L. O., et. al. PNAS 2004, 101, 16721 - 16726

  42. Take Home Message • PSSC group proteins together regardless of primary structure identity • High hit rate achieved from small library size • Compound library was designed to mimic the structure of natural products (NPs)

  43. Second Approach • Structure of NP dictates the way it binds to proteins • Structural classification of natural products (SCONP) Natural inhibitor of Cdc25A Dysidiolide, IC50=9.4μM

  44. Structural Classification of Natural Products (SCONP) • Method • Chose compounds in the Dictionary of Natural Products containing ring structures • Create scaffold map • Properties of SCONP • Structural relationships between different NP classes • Tool for NP derived compound library development

  45. Computational Simulation to Generate SCONP • Deglycosylation prior to running simulation • Neglect stereochemistry • Reduce structural complexity of multi-ring systems • Choose heterocyclic substructures as parent scaffolds

  46. N-Heterocycles Scaffolds of Natural products Carbocycles O-Heterocycles Waldmann, H., et. al. PNAS. 2005, 102, 17272-17277

  47. Implications of SCONP • Parent scaffold represents a substructure of a respective offspring scaffold • Two to four-ring-containing NPs are the most common scaffolds • Scaffolds include the structural information of how NPs bind to proteins

  48. 11βHSD1 • Potential target for treatment of obesity, the metabolic syndrome, and type 2 diabetes • Inhibition of isoenzyme 11βHSD2 causes sodium retention resulting in hypertension

  49. Glycyrrhetinic Acid Glycyrrhetinic Acid (GA) Natural inhibitor of Cdc25A

  50. Glycyrrhetinic Acid Glycyrrhetinic Acid (GA) Natural inhibitor of Cdc25A

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