The Tropical Disease Initiative An open source approach to drug - - PowerPoint PPT Presentation

▶
the tropical disease initiative
SMART_READER_LITE
LIVE PREVIEW

The Tropical Disease Initiative An open source approach to drug - - PowerPoint PPT Presentation

Feb 16, 2024 645 likes •881 views

The Tropical Disease Initiative An open source approach to drug development www.tropicaldisease.org www.thesynapticleap.org Marc A. Marti-Renom http://bioinfo.cipf.es/sgu/ Structural Genomics Unit Bioinformatics Department Prince Felipe

slide-1
SLIDE 1 Marc A. Marti-Renom http://bioinfo.cipf.es/sgu/ Structural Genomics Unit Bioinformatics Department Prince Felipe Resarch Center (CIPF), Valencia, Spain

The Tropical Disease Initiative

An open source approach to drug development www.tropicaldisease.org www.thesynapticleap.org
slide-2
SLIDE 2

SG

slide-3
SLIDE 3

TDI

slide-4
SLIDE 4

Need is High in the Tail

DALY Burden Per Disease in Developed Countries DALY Burden Per Disease in Developing Countries Disease data taken from WHO, World Health Report 2004 DALY - Disability adjusted life years DALY is not a perfect measure of market size, but is certainly a good measure for importance. DALYs for a disease are the sum of the years of life lost due to premature mortality (YLL) in the population and the years lost due to disability (YLD) for incident cases of the health
  • condition. The DALY is a health gap measure that extends the concept of potential years of life lost due to premature death (PYLL) to include equivalent years of 'healthy' life lost in states
  • f less than full health, broadly termed disability. One DALY represents the loss of one year of equivalent full health.
4 Disease DALY Heart diseases Rare diseases
slide-5
SLIDE 5

Need is High in the Tail

DALY Burden Per Disease in Developed Countries DALY Burden Per Disease in Developing Countries Disease data taken from WHO, World Health Report 2004 DALY - Disability adjusted life years DALY is not a perfect measure of market size, but is certainly a good measure for importance. DALYs for a disease are the sum of the years of life lost due to premature mortality (YLL) in the population and the years lost due to disability (YLD) for incident cases of the health
  • condition. The DALY is a health gap measure that extends the concept of potential years of life lost due to premature death (PYLL) to include equivalent years of 'healthy' life lost in states
  • f less than full health, broadly termed disability. One DALY represents the loss of one year of equivalent full health.
4 Disease DALY Heart diseases Rare diseases
slide-6
SLIDE 6

Unprofitable Diseases and Global DALY (in 1000’s)

Malaria*.....................46,486 Syphilis.......................4,200 Chagas Disease*............667 Leishmaniasis*...........2,090 Poliomyelitise...............151 Tetanus........................7,074 Diphtheria.....................185 Trichuriasis.................1,006 Lymphatic filariasis*..5,777 Ascariasis....................1,817 Leprosy*.........................199 Schistosomiasis*.........1,702 Japanese encephalitis...709 Dengue*.........................616 Hookworm disease........59 Trachoma....................2,329 Trypanosomiasis*......1,525 Onchocerciasis*..............484 Disease data taken from WHO, World Health Report 2004 DALY - Disability adjusted life year in 1000’s. * Officially listed in the WHO Tropical Disease Research disease portfolio. 5
slide-7
SLIDE 7 6

Drug Discovery pipeline

Pre Lead Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12 Cumulative cost Success rate Registration Phase III Phase II Phase I Preclinical Lead
  • ptimization
Target & Lead identification Adapted from: - Nwaka & Ridley. (2003) Nature Reviews. Drug Discovery. 2:919
  • Austin, Brady, Insel & collins. (2004) Science. 306:1138
Target & Lead identification Computational Biology Target Inhibitors Iterative Bio/Med chemistry Validated hits Leads Drug candidates Compounds
slide-8
SLIDE 8 7

Drug Discovery pipeline

Pre Lead Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Cumulative cost Success rate Registr Phase III Phase II Phase I Preclinical Lead
  • ptimization
Target & Lead identification shorter time...

TDI

+ Completeness of genome projects (eg, Malaria) + New and more complete biological databases + New software and computers (cheaper and faster) + Internet == more people == less cost
  • Computational Biology alone is not enough
  • TDI needs chemistry and biology! (How?)
slide-9
SLIDE 9 8

TDI flowchart

!"#$%&'() !"#$%&'() !*$+,'%-. !*$+,'%-. databases of genome sequences database of protein structures virtual ligand libraries PubMed, journals
  • ther databases
literature searches sequence similarity searches protein structure modeling protein-ligand docking functional annotation protein production protein engineering compound libraries synthetic chemistry structural biology target validation high-throughput screening substrate specificity studies /%*0*.)

'1% '1%

2%(',304 +"3($3 '*5%!%')43-14 +"3($3!*6%-#'%!4 #230,3'%*- !0%-%!304&',1%#& 1(,.4+(*1,!'%*- 7894: 4:;<=>4 9=?=@:AB=8;4 9=?=@:AB=8;4 :>C78DE7;D:8F @=79F '3(.#'41%&!*2#() 0#3141%&!*2#() 0#314*+'%$%G3'%*- 9>HCF
slide-10
SLIDE 10

Medicines for Malaria Venture

a virtual pharma

9 PSAC antagonist Dihydrofolate reductase Novel macrolides Isoquine (improved aminoquinoline) OZ + PQP RBx11160/ OZ277 + piperaquine Chlorproguanil- dapsone (Lapdap)
  • artesunate (CDA)
Lead identification Lead
  • ptimization
Transition Phase I Phase II Pf enoyl-ACP reductase (Fab i) New dicationic molecules 4(1H)- pyridones Backups AQ-13 new aminoquinoline Paediatric coartem Cyclofarnesyl sequiterpenes Pf protein farnesyl- transferase (Pf-PFT) Falcipain (cysteine protease) Pyronaridine– artesunate Next generation antimalarials Entantio- selective 8-amino- quinolines EuArtekin (dihydroartemisinin–piperaquine) Novel imidazolidine
  • diones
MMV active support ended MMV/GSK portfolio New projects to be added Exploratory Discovery Preclinical Clinical development Phase III Director, Drug Discovery and Technology Contracts Officer Administrative Assistant Director, Clinical Development Director, Clinical Development Associate Director, Clinical Development CEO Administrative Assistant Communication and Advocacy Officer Chief Scientific Officer Chief Finance Officer and Donor Relations Human Resources Officer Director, International Ops From: - Munos (2006) Nature Reviews. Drug Discovery. Open-Source + Out-Source = low cost business model
slide-11
SLIDE 11 10

Do we have the toolbox?

!"#$%&'() !"#$%&'() !*$+,'%-. !*$+,'%-. databases of genome sequences database of protein structures virtual ligand libraries PubMed, journals
  • ther databases
literature searches sequence similarity searches protein structure modeling protein-ligand docking functional annotation protein production protein engineering compound libraries synthetic chemistry structural biology target validation high-throughput screening substrate specificity studies /%*0*.)

'1% '1%

'3(.#'41%&!*2#() 0#3141%&!*2#() 0#314*+'%$%G3'%*- 2%(',304 +"3($3 '*5%!%')43-14 +"3($3!*6%-#'%!4 #230,3'%*- !0%-%!304&',1%#& 1(,.4+(*1,!'%*- 7894: 4:;<=>4 9=?=@:AB=8;4 9=?=@:AB=8;4 :>C78DE7;D:8F
slide-12
SLIDE 12

TDI web site projects

Collaboration tools

Ginger Taylor Collaborative Drug Discovery Barry Bunin Gene Cards Structure Prediction Target Selection for Structural Genomics Gene Annotation Gene Basket Database of annotated chemical compounds
slide-13
SLIDE 13

The Synaptic Leap

  • Non-profit
  • rganization
  • Original volunteers

have commercial portal application background

  • Significant science

partner Tropical Disease Initiative

http://www.thesynapticleap.org 12
slide-14
SLIDE 14

Malaria & Schisto Communities

Schisto Malaria 13 Usefulchem (blog) Chemists
slide-15
SLIDE 15

Collaboration tools

Caution! The following does not exist and is STILL not funded.

14
slide-16
SLIDE 16 15

Gene Board

collecting gene information

  • NCBI at http://www.ncbi.nlm.nih.gov/
  • BioMart at http://www.biomart.org/
  • ModBase at http://www.salilab.org/modbase

Literature Annotation Structure Function

slide-17
SLIDE 17 16

Target Annotation

Gene Wiki

The aim of the project is to provide tools to registered users to manually annotate malaria genes.
slide-18
SLIDE 18 17

Gene Basket

add content to your genes... add genes to your content TSL registered users will be able to save gene cards in their baskets and associate pieces of information to entries in the basket. For example, a user may be browsing the literature at PubMed and find an interesting article, with just
  • ne click the system should be able to propose and
association between the article and any of the genes in his/her basket. As seen on:
slide-19
SLIDE 19 17

Gene Basket

add content to your genes... add genes to your content TSL registered users will be able to save gene cards in their baskets and associate pieces of information to entries in the basket. For example, a user may be browsing the literature at PubMed and find an interesting article, with just
  • ne click the system should be able to propose and
association between the article and any of the genes in his/her basket. As seen on:
slide-20
SLIDE 20 17

Gene Basket

add content to your genes... add genes to your content TSL registered users will be able to save gene cards in their baskets and associate pieces of information to entries in the basket. For example, a user may be browsing the literature at PubMed and find an interesting article, with just
  • ne click the system should be able to propose and
association between the article and any of the genes in his/her basket. As seen on:
slide-21
SLIDE 21 18 !"#$%&'() !"#$%&'() !*$+,'%-. !*$+,'%-. databases of genome sequences database of protein structures virtual ligand libraries PubMed, journals
  • ther databases
literature searches sequence similarity searches protein structure modeling protein-ligand docking functional annotation protein production protein engineering compound libraries synthetic chemistry structural biology target validation high-throughput screening substrate specificity studies /%*0*.)

'1% '1%

2%(',304 +"3($3 '*5%!%')43-14 +"3($3!*6%-#'%!4 #230,3'%*- !0%-%!304&',1%#& 1(,.4+(*1,!'%*- 7894: 4:;<=>4 9=?=@:AB=8;4 9=?=@:AB=8;4 :>C78DE7;D:8F @=79F '3(.#'41%&!*2#() 0#3141%&!*2#() 0#314*+'%$%G3'%*- 9>HCF
slide-22
SLIDE 22

Acknowledgments

Tropical Disease Initiative Barry Bunin (CDD) Moses M. Hohman (CDD) Thomas Kepler (Duke U) Marc A. Marti-Renom (CIPF) Stephen Maurer (Berkeley) Jim McKerrow (UCSF) John P. Overington (Impharmatica Inc.) Arti Rai (Duke U) David Roos (U Penn) Andrej Sali (UCSF) Brian Schoichet (UCSF) Wiki site at NPG Timo Hannay Declan Butler The Synaptic Leap Ginger Taylor (Founder) Jean-Claude Bradley (Chemistry) Sebastian Jayaraj (Coder) Thomas Kepler (Board) Marc A. Marti-Renom (Advisor) Stephen Maurer (Advisor) Miguel Miychell (Tuberculosis) Arti Rai (Board) Saj Sajid (Malaria) Matt H. Todd (Schisto) Read more @
  • PLoS Medicine, Dec. 2004. Vol 1(3):e56
  • The Economist (June 10, 2004)
  • Aust. J. Chem, 2006. Vol 59:291
“Put a description of your paper on a weblog, and something very different happens. People who are very far afield from your usual circle start thinking about the subject . They bring up interesting perspectives. ” Paul Meyers (Nature, vol 438, p549) http://www.tropicaldisease.org http://www.thesynapticleap.org http://bioinfo.cipf.es/sgu/