biology oriented synthesis a new approach to drug design n.
Download
Skip this Video
Download Presentation
Biology Oriented Synthesis A New Approach to Drug Design

Loading in 2 Seconds...

play fullscreen
1 / 60

Biology Oriented Synthesis A New Approach to Drug Design - PowerPoint PPT Presentation


  • 78 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Biology Oriented Synthesis A New Approach to Drug Design' - francesca-key


Download Now An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
biology oriented synthesis a new approach to drug design

Biology Oriented SynthesisA New Approach to Drug Design

Ruoying Gong

Department of Chemistry

March 12, 2009

what is a drug
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

drug discovery
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

rational drug design process

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

rational drug design process1

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

drawback of rational drug design
Drawback of Rational Drug Design
  • Time consuming
  • Costly
  • Limited understanding of drug receptors
  • Labour intensive
  • Low hit rate generated
new approach to drug design
New Approach to Drug Design
  • Novel approach
    • Biology oriented synthesis
  • Created by Waldmann group
    • Max Planck Institute, Germany
drug and drug receptor
Drug and Drug Receptor
  • Knowledge of 3D structure of protein can assist in the design of drug scaffold

Protein

Catalytic core

Ligand binding site

protein structure
Protein Structure

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

protein classification

Protein 1

  • Protein 3
Protein Classification
  • Protein 2
  • Protein family

Similar 3D structure,

function, and

primary structure

proteins in the same family
Proteins In the Same Family
  • Similar mechanism
  • Similar primary structure
  • Similar 3D structure
  • Similar amino acid residues
process of ligand discovery
Process of Ligand Discovery

Target

Protein

Model Protein

waldmann approach
Waldmann Approach
  • Compare proteins with their 3D structure
  • Use a natural inhibitor as guiding structure for compound library development
protein domain and fold
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

protein structure architecture
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

superfold and supersite
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

classification comparison
Classification Comparison

Protein Family

  • Similar primary structure
  • Similar ligand binding site

Protein Fold

  • Not related to primary structure
  • Similar ligand binding site
biology oriented synthesis
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

grouping proteins together
Grouping Proteins Together
  • Protein Structure Similarity Clustering (PSSC)
    • 3D similarity of ligand binding sites
    • Ignore the amino acid sequence identity
computation tools used
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
protein clustering process

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

1 protein of interest cdc25a
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

2 structure alignment
2.Structure Alignment
  • Cdc25A
  • AChE
  • 11βHSD1,2
3 acetylcholinesterase ache
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

4 superimposition
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

2 structure alignment1
2.Structure Alignment
  • Cdc25A
  • AChE
  • 11βHSD1,2
  • 11βHSD1,2
3 isoenzymes 11 hsd1 2
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

11 hsd1
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

11 hsd2
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

4 superimposition1
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

structure alignment
Structure Alignment
  • Cdc25A
  • AChE
  • 11βHSD1,2
  • 11βHSD1,2
superimposition
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

dysidiolide natural inhibitor of cdc25a
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

dysidiolide natural inhibitor of cdc25a1
Dysidiolide: Natural Inhibitor of Cdc25A

γ-hydroxybutenolide

α,β-Unsaturated lactone

Brohm, D., et. al. Angew. Chem. Int. Ed. 2002, 41, 307 - 311

hydroxybutenolides synthesis
γ-Hydroxybutenolides Synthesis

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

unsaturated lactones synthesis
α,β-Unsaturated Lactones Synthesis

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

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

take home message
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)
second approach
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

structural classification of natural products sconp
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
computational simulation to generate sconp
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
slide46

N-Heterocycles

Scaffolds of

Natural products

Carbocycles

O-Heterocycles

Waldmann, H., et. al. PNAS. 2005, 102, 17272-17277

implications of sconp
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
11 hsd11
11βHSD1
  • Potential target for treatment of obesity, the metabolic syndrome, and type 2 diabetes
  • Inhibition of isoenzyme 11βHSD2 causes sodium retention resulting in hypertension
glycyrrhetinic acid
Glycyrrhetinic Acid

Glycyrrhetinic Acid (GA)

Natural inhibitor of Cdc25A

glycyrrhetinic acid1
Glycyrrhetinic Acid

Glycyrrhetinic Acid (GA)

Natural inhibitor of Cdc25A

glycyrrhetinic acid2
Glycyrrhetinic Acid

Glycyrrhetinic Acid (GA)

Natural inhibitor of Cdc25A

scaffolds of natural products
Scaffolds of Natural Products

Carbocycles

Waldmann, H., et. al. PNAS. 2005, 102, 17272-17277

scaffolds of natural products1
Scaffolds of Natural Products

Dysidiolide

Natural inhibitor of Cdc25A

Glycyrrhetinic Acid (GA)

Natural inhibitor of Cdc25A

?

Waldmann, H., et. al. PNAS. 2005, 102, 17272-17277

compound library synthesis
Compound Library Synthesis

Waldmann, H., et. al. PNAS. 2005, 102, 17272-17277

library general structure
Library General Structure

Waldmann, H., et. al. PNAS. 2005, 102, 17272-17277

results1
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
best compounds1
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, 17272-17277

combined with pssc and sconp
Combined With PSSC and SCONP

PSSC

Natural inhibitor

Target

Compound Library

Biology

Oriented Synthesis

(BIOS)

Biology

Chemistry

Nören-Müller, et. al. PNAS. 2006, 103, 10606-10611

conclusion
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
acknowledgement
Acknowledgement
  • Dr. Robert Ben
  • Dr. Mathieu Leclere
  • Roger Tam
  • Jennifer Chaytor
  • Elisabeth von Moos
  • PawelCzechura
  • John Trant
  • Wendy Campbell
  • Sandra Ferreira
  • TalineBoghossian
  • Jackie Tokarew