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 Resarch Center (CIPF), Valencia, Spain
SG
TDI
Need is High in the Tail DALY Burden Per Disease in Developed Countries DALY Burden Per Disease in Developing Countries Heart diseases Rare diseases DALY Disease 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 of less than full health, broadly termed disability. One DALY represents the loss of one year of equivalent full health. 4
Need is High in the Tail DALY Burden Per Disease in Developed Countries DALY Burden Per Disease in Developing Countries Heart diseases Rare diseases DALY Disease 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 of less than full health, broadly termed disability. One DALY represents the loss of one year of equivalent full health. 4
Unprofitable Diseases and Global DALY (in 1000 ’ s) Ascariasis....................1,817 Malaria*.....................46,486 Leprosy*.........................199 Syphilis.......................4,200 Schistosomiasis*.........1,702 Chagas Disease*............667 Japanese encephalitis...709 Leishmaniasis*...........2,090 Dengue*.........................616 Poliomyelitise...............151 Hookworm disease........59 Tetanus........................7,074 Trachoma....................2,329 Diphtheria.....................185 Trypanosomiasis*......1,525 Trichuriasis.................1,006 Onchocerciasis*..............484 Lymphatic filariasis*..5,777 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
Drug Discovery pipeline Cumulative cost Success rate 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 Lead Target & Lead Preclinical Phase I Phase II Phase III Registration optimization identification Target & Lead identification Computational Biology Iterative Bio/Med chemistry Target Inhibitors Validated hits Leads Drug candidates Compounds Adapted from: - Nwaka & Ridley. (2003) Nature Reviews. Drug Discovery . 2 :919 - Austin, Brady, Insel & collins. (2004) Science . 306 :1138 6
Drug Discovery pipeline Cumulative cost Success rate shorter time... Pre Lead Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Lead Target & Lead Preclinical Phase I Phase II Phase III Registr optimization identification 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?) 7
TDI flowchart databases of genome sequences database of protein structures virtual ligand libraries PubMed, journals other databases sequence similarity searches protein structure modeling literature searches protein-ligand docking 2%(',304 functional annotation +"3($3 !*$+,'%-. !*$+,'%-. '1% '1% 7894: 4:;<=>4 9=?=@:AB=8;4 9=?=@:AB=8;4 :>C78DE7;D:8F @=79F '*5%!%')43-14 +"3($3!*6%-#'%!4 '3(.#'41%&!*2#() #230,3'%*- 0#3141%&!*2#() 0#314*+'%$%G3'%*- !0%-%!304&',1%#& 1(,.4+(*1,!'%*- synthetic chemistry compound libraries high-throughput screening 9>HCF !"#$%&'() !"#$%&'() protein production protein engineering substrate specificity studies structural biology target validation /%*0*.) 8
Medicines for Malaria Venture a virtual pharma Open-Source + Out-Source = low cost business model Exploratory Discovery Preclinical Clinical development Lead Lead CEO Transition Phase I Phase II Phase III identification optimization OZ + PQP Chlorproguanil- Chief Finance O ffi cer and Isoquine Administrative Assistant PSAC Dihydrofolate Novel RBx11160/ dapsone Donor Relations (improved antagonist reductase macrolides OZ277 (Lapdap) aminoquinoline) + piperaquine -artesunate (CDA) Communication Human Resources O ffi cer Pf enoyl-ACP New 4(1H)- and Advocacy O ffi cer AQ-13 new Paediatric reductase dicationic pyridones aminoquinoline coartem (Fab i) molecules Backups Chief Scientific O ffi cer Director, International Ops Pf protein Falcipain Cyclofarnesyl farnesyl- Pyronaridine– (cysteine sequiterpenes transferase artesunate protease) ( Pf -PFT) Director, Drug Discovery Director, Clinical Entantio- Next and Technology Development selective generation EuArtekin (dihydroartemisinin–piperaquine) 8-amino- antimalarials quinolines Director, Clinical Contracts O ffi cer Development Novel imidazolidine -diones Associate Director, Administrative Assistant Clinical Development MMV active support ended MMV/GSK portfolio New projects to be added From: - Munos (2006) Nature Reviews. Drug Discovery . 9
Do we have the toolbox? databases of genome sequences database of protein structures virtual ligand libraries PubMed, journals other databases 2%(',304 sequence similarity searches protein structure modeling +"3($3 literature searches protein-ligand docking functional annotation !*$+,'%-. !*$+,'%-. 7894: 4:;<=>4 '1% '1% 9=?=@:AB=8;4 9=?=@:AB=8;4 :>C78DE7;D:8F '*5%!%')43-14 '3(.#'41%&!*2#() +"3($3!*6%-#'%!4 0#3141%&!*2#() 0#314*+'%$%G3'%*- #230,3'%*- !0%-%!304&',1%#& synthetic chemistry compound libraries high-throughput screening 1(,.4+(*1,!'%*- !"#$%&'() !"#$%&'() protein production protein engineering substrate specificity studies structural biology target validation /%*0*.) 10
TDI web site projects Collaboration tools Gene Cards Structure Prediction Ginger Taylor Target Selection for Structural Genomics Gene Annotation Collaborative Drug Discovery Gene Basket Barry Bunin Database of annotated chemical compounds
The Synaptic Leap • Non-profit http://www.thesynapticleap.org organization • Original volunteers have commercial portal application background • Significant science partner Tropical Disease Initiative 12
Malaria & Schisto Communities Malaria Schisto Usefulchem Chemists (blog) 13
Collaboration tools Caution! The following does not exist and is STILL not funded. 14
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 15
Target Annotation Gene Wiki The aim of the project is to provide tools to registered users to manually annotate malaria genes. 16
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 one 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: 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 one 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: 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 one 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: 17
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