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Biology Oriented Synthesis A New Approach to Drug Design

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Presentation on theme: "Biology Oriented Synthesis A New Approach to Drug Design"— Presentation transcript:

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

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

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 Catalytic core Protein Ligand binding site

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

10 Protein Classification
Similar 3D structure, function, and primary structure Protein family

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
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
(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,

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
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,

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

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,

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,

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

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,

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,

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,

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

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,

33 Cluster Member Comparison
Cdc25A AChE 11βHSD1,2 Protein family Phosphatase α/β-hydrogenase Hydroxysteroid dehydrogenase Sequence identity - 17% 6% RMSD 2.6Å 4.9Å AChE 11βHSD1,2 Sequence identity - 6% RMSD 3.9Å

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,

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

37 Representative Synthesis

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

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

40 Results 147 compounds synthesized
Contains γ-hydroxybutenolide or α,β-unsaturated lactone Inhibitors with these structures have never been reported Cdc25A AChE 11βHSD1 11βHSD2 Hits (rate) 42(28.5%) 3 (2%) 3(2%) 4(2%)

41 Natural inhibitor of Cdc25A
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,

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 Natural inhibitor of Cdc25A
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 Scaffolds of Natural products N-Heterocycles Carbocycles
O-Heterocycles Waldmann, H., et. al. PNAS. 2005, 102,

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

51 Glycyrrhetinic Acid Glycyrrhetinic Acid (GA)
Natural inhibitor of Cdc25A

52 Scaffolds of Natural Products
Carbocycles Waldmann, H., et. al. PNAS. 2005, 102,

53 Scaffolds of Natural Products
Dysidiolide Natural inhibitor of Cdc25A Glycyrrhetinic Acid (GA) Natural inhibitor of Cdc25A ? Waldmann, H., et. al. PNAS. 2005, 102,

54 Compound Library Synthesis
Waldmann, H., et. al. PNAS. 2005, 102,

55 Library General Structure
Waldmann, H., et. al. PNAS. 2005, 102,

56 Results 162 members synthesized with the simple bicycle ring scaffold
28 compounds selectively inhibit 11βHSD1 Inhibitors with this bicycle ring scaffold have never been reported 11βHSD1 11βHSD2 Hits (rate) 30(18.5%) 3(2%)

57 Best Compounds Glycyrrhetinic Acid (GA) Natural inhibitor of Cdc25A
11βHSD1, IC50=0.31μM 11βHSD2, IC50=6.6μM 11βHSD1, IC50=0.74μM 11βHSD2, IC50>30μM 11βHSD1, IC50=0.35μM 11βHSD2, IC50>30μM Waldmann, H., et. al. PNAS. 2005, 102,

58 Combined With PSSC and SCONP
Natural inhibitor Compound Library Target Biology Oriented Synthesis (BIOS) Biology Chemistry Nören-Müller, et. al. PNAS. 2006, 103,

59 Conclusion PSSC classifies proteins together by 3D similarity of ligand binding site SCONP is a guiding tool for NP derived compound library development Small compound libraries synthesized generate high hit rates for proteins from different families The chemical and biological approaches of BIOS were useful for the synthesis of drug-like compounds

60 Acknowledgement Dr. Robert Ben Dr. Mathieu Leclere Roger Tam
Jennifer Chaytor Elisabeth von Moos Pawel Czechura John Trant Wendy Campbell Sandra Ferreira Taline Boghossian Jackie Tokarew

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