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Worldwide Protein Data Bankwww.wwpdb.org
Computational BiologyPhilip E. Bourne PhD
pbourne@ucsd.edu
http://www.sdsc.edu/pb
02/07/2011 Computational Biology Summit Chattanooga
Thanks to Howard Asher for some slides
Agenda
Computational Biology
– What is it?
– What are some success stories to date
– What pitfalls can be avoided based on the experiences of others
– What opportunities does it afford the region from a research, education and hence economic perspective?
02/07/2011 Computational Biology Summit Chattanooga
Biology has moved from being an observational to an analytical science
02/07/2011 Computational Biology Summit Chattanooga
Biology covers vast scales
02/07/2011 Computational Biology Summit Chattanooga
02/07/2011 Computational Biology Summit Chattanooga
Comparative Genomics
Neural Circuits
Biochemical pathways underlying drug addiction
Adaptive fast walking
Object recognition
Biologics
Worldwide Protein Data Bankwww.wwpdb.org
What drove these research directions?
02/07/2011 Computational Biology Summit Chattanooga
Technologies
producing
digital
Information
02/07/2011 Computational Biology Summit Chattanooga
Num
ber
of r
elea
sed
entr
ies
Year
Its not just about numbers its about complexity
Courtesy of the RCSB Protein Data Bank
02/07/2011 Computational Biology Summit Chattanooga
June 26, 2000 was a milestone with the mapping of the human genome
U.S. President Bill Clinton listens to British Prime Minister Tony Blair as Celera President J Craig Venter looks on during a joint teleconference announcement in the East Room of the White House, June 26, 2000. Venter's company Celera Genomics Corporation participated in a publicly financed Human Genome Project with private efforts and have both completed the first rough map of the human genome, the working blueprint for human beings. The discovery is seen as one of history's great scientific milestones.
British Prime Minister Tony Blair
Announced by then US president Bill Clinton and the British Prime Minister Tony Blair
02/07/2011
Today informatics ≥ 2 x data ≅3 months
Subdisciplines of “matics”
Computational Biology Summit Chattanooga
PharmacyInformatics
BiomedicalInformatics
Bioinformatics
Drug dosingPharmacokineticsPharmacy InformationSystems
Electronic HRDecision support
AlgorithmsGenomicsProteomicsSystems
Note: These are only representative examples
Agenda
Computational Biology
– What is it?
– What are some success stories to date
– What pitfalls can be avoided based on the experiences of others
– What opportunities does it afford the region from a research, education and hence economic perspective?
02/07/2011 Computational Biology Summit Chattanooga
Metagenomics
New type of genomics New data (and lots of
it) and new types of data– 17M new (predicted
proteins!) 4-5 x growth in just few months and much more coming
– New challenges and exacerbation of old challenges
Metagenomics: early results
More then 99.5% of DNA in every environment studied represent unknown organisms
Most genes represent distant homologs of known genes, but there are thousands of new families
Environments being studied:– Water (ocean, lakes)– Air– Soil– Human body (gut, oral
cavity, human microbiome)
Metagenomics new discoveriesEnvironmental (red) vs. Currently Known PTPases (blue)
Higher eukaryotes
1
23
4
Personalized medicine
Personalized medicine
Right Therapeutic—Right Dose—Right Time—Right Place—Right Person& Understanding of genetic contributions to disease and to its treatment…
02/07/2011 Computational Biology Summit Chattanooga
Your health—optimized to you
02/07/2011 Computational Biology Summit Chattanooga
Worldwide Protein Data Bankwww.wwpdb.org
We know very little about how the major drugs we take work
We know even less about their side effects Drug discovery seems not to have moved into
the omics era The cost and time of bringing a drug to market
is huge ~ $1 Bn The cost of failure is even higher e.g., Vioxx
~ $5 Bn Fatal diseases are neglected because they do
not make money
Drug discovery – the sad truth
02/07/2011 Computational Biology Summit Chattanooga
Worldwide Protein Data Bankwww.wwpdb.org
Why the failure?
02/07/2011 Computational Biology Summit Chattanooga
Polypharmacology - One Drug Binds to Multiple Targets
• Tykerb – Breast cancer
• Gleevac – Leukemia, GI cancers
• Nexavar – Kidney and liver cancer
• Staurosporine – natural product – alkaloid – uses many e.g., antifungal antihypertensive
Collins and Workman 2006 Nature Chemical Biology 2 689-700
Worldwide Protein Data Bankwww.wwpdb.org
Why the failure?
What can be done about it?
02/07/2011 Computational Biology Summit Chattanooga
High-throughput computational drug discovery can Be applied on three axes
Target
Disease
Drug
Cheminfomatics
HTS
Docking
One to Multiple TargetsBioinformatics
Associative Transfer of Indications
Worldwide Protein Data Bankwww.wwpdb.org
Consider one example of using the corpus as a whole from our own research – high throughput hypothesis generation for use in drug discovery
02/07/2011 Computational Biology Summit Chattanooga
The TB-Drugome
1. Determine the TB structural proteome
2. Determine all known drug binding sites from the PDB
3. Determine which of the sites found in 2 exist in 1
4. Call the result the TB-drugomeKinnings et al 2010 PLoS Comp Biol 6(11): e1000976
Computational Biology Summit Chattanooga
02/07/2011
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 370
20
40
60
80
100
120
140
2. Determine all Known Drug Binding Sites in the PDB
Searched the PDB for protein crystal structures bound with FDA-approved drugs
268 drugs bound in a total of 931 binding sites
No. of drug binding sites
No.
of
drug
s
MethotrexateChenodiol
AlitretinoinConjugated estrogens
DarunavirAcarbose
02/07/2011 Computational Biology Summit Chattanooga
Map 2 onto 1 – The TB-Drugomehttp://funsite.sdsc.edu/drugome/TB/
Similarities between the binding sites of M.tb proteins (blue), and binding sites containing approved drugs (red).
1 2 3 4 5 6 7 8 9 10 11 12 13 140
2
4
6
8
10
12
14
16
18
20
From a Drug Repositioning Perspective
Similarities between drug binding sites and TB proteins are found for 61/268 drugs
41 of these drugs could potentially inhibit more than one TB protein
No. of potential TB targets
No.
of
drug
s
raloxifenealitretinoin
conjugated estrogens &methotrexate
ritonavir
testosteronelevothyroxine
chenodiol
02/07/2011
Top 5 Most Highly Connected Drugs
Drug Intended targets Indications No. of connections TB proteins
levothyroxine transthyretin, thyroid hormone receptor α & β-1, thyroxine-binding globulin, mu-crystallin homolog, serum albumin
hypothyroidism, goiter, chronic lymphocytic thyroiditis, myxedema coma, stupor
14
adenylyl cyclase, argR, bioD, CRP/FNR trans. reg., ethR, glbN, glbO, kasB, lrpA, nusA, prrA, secA1, thyX, trans. reg. protein
alitretinoin retinoic acid receptor RXR-α, β & γ, retinoic acid receptor α, β & γ-1&2, cellular retinoic acid-binding protein 1&2
cutaneous lesions in patients with Kaposi's sarcoma 13
adenylyl cyclase, aroG, bioD, bpoC, CRP/FNR trans. reg., cyp125, embR, glbN, inhA, lppX, nusA, pknE, purN
conjugated estrogens
estrogen receptormenopausal vasomotor symptoms, osteoporosis, hypoestrogenism, primary ovarian failure
10acetylglutamate kinase, adenylyl cyclase, bphD, CRP/FNR trans. reg., cyp121, cysM, inhA, mscL, pknB, sigC
methotrexatedihydrofolate reductase, serum albumin
gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, severe psoriasis, rheumatoid arthritis
10acetylglutamate kinase, aroF, cmaA2, CRP/FNR trans. reg., cyp121, cyp51, lpd, mmaA4, panC, usp
raloxifeneestrogen receptor, estrogen receptor β
osteoporosis in post-menopausal women 9
adenylyl cyclase, CRP/FNR trans. reg., deoD, inhA, pknB, pknE, Rv1347c, secA1, sigC
02/07/2011 Computational Biology Summit Chattanooga
Agenda
Computational Biology
– What is it?
– What are some success stories to date
– What pitfalls can be avoided based on the experiences of others
– What opportunities does it afford the region from a research, education and hence economic perspective?
02/07/2011 Computational Biology Summit Chattanooga
1985 1990 1995 2000 2005 2010
Cray-XMP48220 Mflops
Cray C905 Gflops
Cray T3E1 Tflops
SDSC Abbreviated Timeline
http://www.sdsc.edu/News%20Items/PR101510_25years.html
SDSC Lessons Learned
There is a tension between engineering and science – you need people at the interface
People and the services they provide are what make the difference
Fundamental shift from computer speed to data storage
The future is open with provenance Beware the cloud
02/07/2011 Computational Biology Summit Chattanooga
SDSC lessons learned
More focus on education
More focus on integration with surrounding communities
More focus on outreach
02/07/2011 Computational Biology Summit Chattanooga
Agenda
Computational Biology
– What is it?
– What are some success stories to date
– What pitfalls can be avoided based on the experiences of others
– What opportunities does it afford the region from a research, education and hence economic perspective?
02/07/2011 Computational Biology Summit Chattanooga
From the Art of Medicine to the Science of Health…
Genomic Era
Data Information Knowledge Wisdom
Art Transformation Science
2010 the Tipping Point
20202000Art ofMedicineat theorgan level
Science ofHealthat the
molecular level 2010
Worldwide Protein Data Bankwww.wwpdb.org
How to take advantage of this change?
Pick important problems and become a source of valuable data and human resources for solving those problems
Depositor locations
Download locations
RCSB PDB
PDBe
PDBj
Depositions since 2000
02/07/2011 Computational Biology Summit Chattanooga
Worldwide Protein Data Bankwww.wwpdb.org
How to take advantage of this change?
Enable the use of those data and resources in ways that the next generation will build upon
www.scivee.tv
02/07/2011 Computational Biology Summit Chattanooga
Enjoy the ah ha moments
Acknowledgements
Funding Agencies: NSF, NIGMS, DOE, NLM, NCI, NCRR, NIBIB, NINDS, NIDDK
4402/07/2011 Computational Biology Summit Chattanooga
Questions?
pbourne@ucsd.edu
02/07/2011 Computational Biology Summit Chattanooga
What is the Protein Data Bank (PDB)?
The single community owned worldwide repository on the structures of publically accessible biological macromolecules
A resource used by ~ 200,000 individuals per month
A resource distributing equivalent to ¼ the National Library of Congress each month
02/07/2011 Computational Biology Summit Chattanooga
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