slide1 l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
FRAGMENT- BASED DRUG DESIGN PowerPoint Presentation
Download Presentation
FRAGMENT- BASED DRUG DESIGN

Loading in 2 Seconds...

play fullscreen
1 / 55

FRAGMENT- BASED DRUG DESIGN - PowerPoint PPT Presentation


  • 260 Views
  • Uploaded on

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 ).

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 'FRAGMENT- BASED DRUG DESIGN' - tracey


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
fragment based drug design

FRAGMENT- BASED DRUG DESIGN

Yemane MengistuMichigan State UniversityJanuary 30, 2008

annual research and development expense
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 )

drug discovery process
Drug Discovery Process

Combinatorial Chemistry

Natural products

High-throughput

Screening (HTS)

  • Target molecule
  • eg. Enzymes

Toxicity Clinical trials

Lead &

Drug

optimization

creating a library
Creating a Library

A Natural Product

Thymidinyl nucleoside

Sun, D., Lee, R.E. Tetrahedron Lett. 2005, 46, 8497-8501

slide6

Creating a Library Using Ugi Chemistry

Thymidinyl nucleoside library

creating a library using ugi chemistry
Creating a Library Using Ugi Chemistry

Walters, W.P., Stahl, M.T., Murcko, M.A. Drug Discovery Today1998, 3,160-178

creating a thymidinyl ugi library
Creating a Thymidinyl Ugi Library

Sun, D., Lee, R.E. Tetrahedron Lett. 2005, 46, 8497-8501

thymidinyl ugi library
Thymidinyl Ugi Library

Sun, D.; Lee, R.E. Tetrahedron Lett. 2005, 46, 8497-8501

high throughput screening hts
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

slide12

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.

slide13

1µM

10 nM

1mM

600

Drug

Candidates

HTS

hits

Drugs

500

Lead optimization

400

Relative Molecular Mass

300

200

HTS Library

100

0

Potency

a typical drug discovery cascade
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

slide15
HTS

GlaxoSmithKline’s HTS Scoreboard

Chemical engineering news, 2004, 82 ,23-32

fragnomics fragment based drug design
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

mw of average hts hits and fragments

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

fragnomics fragment based drug design18
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
fragnomics fragment based drug design19
Fragnomics: Fragment Based Drug Design

Conventional HTS approach Fragment based drug design

Swayze, E.E, et al.J.Med.Chem. 2003, 46, 4232-4235

what qualifies compounds to be fragments
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

what qualifies compounds to be fragments21
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

what qualifies compounds to be fragments22
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

some common drug based fragments
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

conventional hts vs fragonomics based on central scaffold
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

conventional hts drug design
Conventional (HTS) Drug Design

Erlanson, D.A, Hansen, K.S. Curr Opin Chem Biol. 2004, 8,399-406.

conventional hts and fragment based drug design
Conventional (HTS) and Fragment Based Drug Design

Erlanson, D.A, Hansen, K.S. Curr Opin Chem Biol. 2004, 8,399-406.

fragment based drug design27
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

fragment based drug design28
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

fragment based drug design29
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

fragment based drug design30
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

application of fragment based drug design
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

library for the protein kinase inhibitor
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

library for the protein kinase inhibitor33
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

library of protein kinase inhibitor
Library of protein kinase inhibitor

D.J.Maly, I.C.Choong and J.A, Ellman,Proc.Natl.Acad.Sci.USA,2000,97,2419-2424

fragment based design protein kinase inhibition
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

application of fragment based drug design37
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

application of fragment based drug design38
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

application of fragment based drug design39
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

application of fragment based drug design40
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.

application of fragment based drug design41
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

preparation of disulfide containing library members
Preparation of Disulfide-Containing Library Members

Parlow, J.J. & Normansell, J.E.Mol.Diversity 1995,1, 266-269

synthesis of sulfonyl libraries
Synthesis of Sulfonyl Libraries

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

thymidylate synthase inhibitor
Thymidylate Synthase Inhibitor

Selected Non selected

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

thymidylate synthase inhibitor46
Thymidylate Synthase Inhibitor

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

application of fragment based drug design47
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

tethering with extenders dynamically assembling fragments
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.

slide50

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

slide51

Assembling the inhibitor

Erlanson, D.A, Lam, J.W, Wesmann ,C. Nat. Biotechnol. 2003, 21, 308-314

slide52

Assembling the inhibitor

Erlanson, D.A, Lam, J.W, Wesmann ,C. Nat. Biotechnol. 2003, 21, 308-314

caspase 3
Caspase-3

Superimposition of Inhibitor 1(Gray) and compound 4 (salmon) with Capsase 3

Erlanson, D.A, Lam, J.W, Wesmann ,C. Nat.Biotechnol.2003 , 21,308-314

summary
Summary
  • The use of fragment based drug design accompanied by different means of detection could increase the chance of finding new medical entities.
  • Site directed ligand discovery and fragment based lead discovery are still in their infancy, but the success of these emerging approaches could success.
  • No single technology will suffice, and the combination of HTS, site directed , and fragment-based lead discovery will likely become increasingly important.
acknowledgements
Acknowledgements
  • Prof. Kevin D. Walker
  • Prof. Babak Borhan
  • Prof. Bill Wulff
  • Prof. Bob Hausinger
  • Dr. Philip J. Hajduk , Abbott Laboratories
  • Lab members:,Mark, Irosha, Washington, Danielle, Behnaz
  • Friends: Khassay, Mercy, Rahman, Anil, Munmun, Luis