Transcript 08-08-2011-OSDD

Team India Consortium with Global Partnership
A CSIR-led initiative for affordable healthcare to the developing world
Council of Scientific and Industrial Research
INDIA
http://www.osdd.net
“When it comes to health, we need to have a
balanced view between health as a right and
health as a business”
Prof Samir Brahmachari
Director General, CSIR and
Chief Mentor, OSDD
(Ref: Cell (2008) v.133, pp. 201-203)
50
One person
every 20 seconds
TB Kills
1.7 Million people
every year
In India
Nearly 1000 people
every day
Two people
every 3 minutes
Image Credits: Teseum/Flick
Deaths due to Tuberculosis in 2008
Source: GlobalHealthFacts.org
 More than 2 billion people (~1/3 of world population) is affected with the
tubercle bacilli
TB Drug Discovery
“Generations of advances in research and technology
have bypassed TB research” - Anthony Fauci, NIAID .
“The field has been too isolated and inward-looking” Dr.
Margaret Chan, head WHO
Why Open Source Drug discovery ?
 Many eye balls make the bug shallow!
 Lack of market incentive for TB
 Successful Open Source Models
 Human Genome Sequencing Initiative
 Open Source Software Initiative (eg: Linux OS)
 Android
 The WWW
OSDD Approach to Drug Discovery: A New Paradigm
High Risk,
Innovation Driven
Sphere
Process Oriented Activity
Strategy > Open
Innovation with
best minds from
academia/ industry
Development
Strategy>
Industry/CRO’s
Participation- Open
Data- community
inputs
Clinical Trials Strategy>
Public funds to support
clinical trials led by public
funded institutions in
collaboration with CROs/
pharma for process
accuracy.
Registered Drug
Clinical Trials
Optimised Candidate Drug
Validated/ Quality Lead Market Strategy > Generic
industry to manufacture
Hit(s)
drugs with more than one
Target Validation
player for market
Target Identification
competition.
Biology/ Genomics
OSDD Platform
System Architecture
Collaborative tools to accelerate neglected diseases research” in the book “Collaborative
Computational Technologies for Biomedical Research”. Wiley and Sons. 2011 (in press).
OSDD: Attribution and IP
• All contributions on the OSDD portal
attributed to the authors with date and time
stamp
• Real time data sharing
• Click wrap license agreement
– All contributions treated as Protected Collective
Information
• mandates sharing,
• attribution,
• contribute back
OSDD View on Patents
• Two patent applied molecules in hit to lead phase
• Patent only to ensure that:
– Quality assurance in downstream processes
– Subsequent innovations remain in open source
– Affordability : through non exclusive licenses
OSDD – Multipronged approaches
DRUG TARGET
BASED
(18 Drug Targets)
LIGAND BASED
(Pubchem Bioassay
Data/New inhibitors/)
Potential hit
NATURAL PRODUCT
BASED (135
Phytomolecules )
Lead Optimization
Community peer review
Open Funding Review
OSDD Open Access Resources
Assembly line for drug discovery
I
Biological Repository
i. Open access clinical strains repository
ii. Open access clone repository
iii. Open access protein repository
II
Chemical Repository
i. Open access small molecule repository
III
Open Screening Facility
i. Submit your compounds for anti-tuberculosis
screening
Computational Resources developed with
Community participation
http://tbrowse.osdd.net
Bhardwaj et al. Tuberculosis (Edinb). 2009
Sep;89(5):386-7
Chembio
Toolkit
Workflow
engine with federated
http://sysborg2.osdd.net
Bhardwaj et al. 2011 John Wiley & Sons, Inc.
TrapTB
Mtb drug targets database
resources
AmPhyDB
Mtb essen\tial genes database
Antimycobacterial Phytomolecule
Database
Databases Do not “talk” to each other
COG
Mycobacterial Genome
Divergence Database
Easy RNA Profile IdentificatioN
Database of Conditionally
Regulated Proteins
Pathway network &
Unique pathways
Operon predictions
(DOOR/VIMSS/Rutherford)
Drug Targets (TDR/Plos/TDI)
* This is representative set of post-genomics data available on TB
Databases now do “talk” to each other !!
Mycobacterial Genome
Divergence Database
COG
Easy RNA Profile IdentificatioN
Database of Conditionally
Regulated Proteins
Pathway network &
Unique pathways
Operon predictions
(DOOR/VIMSS/Rutherford)
More than 100 datasets
encompassing a million data
points
Drug Targets (TDR/Plos/TDI)
DeekshaBhartiya
Deeksha Bhartiya Nitin Kumar
OpenLabNoteBook on SysBorgTB
http://sysborgtb.osdd.net/bin/view/OpenLabNotebook/TBMapDataset
The “Connect to Decode” Programme
Literature
Annotation
Tools
Genomic
Databases
OSDD C2D
Community
800+
Student
Researcher
s
Collaborative
Curation
Curated
Annotations
Raw
Annotations
Pathway/Interactome | Gene Ontology | Protein
Structure/Fold | Glycomics| Immunome
“Given enough eyeballs, all bugs are
shallow”
-Linus Torvalds
Errors are
Discussed by the
Community
Errors are
corrected by the
Community
Errors are marked
by the
Community for
Correction
Innovative Crowd Sourcing Model for Mtb Systems
Biology
Collaborative Curation
Literature
Curated
Annotations
Annotation
Tools
Genomic
Databases
Community of >800
student researchers
Raw
Annotations
87% of Mtb genome annotated
Generated the largest Interactome & Metabolic Map of Mtb
Within weeks, 830 volunteered to re-annotate the entire M.
tuberculosis genome. The work started in December 2009 and was
completed by April 2010, packing nearly 300 man-years into 4
months!
Source: Munos B. Can Open-Source Drug R&D
Repower Pharmaceutical Innovation?
Clin Pharmacol Ther 2010;87:534–536
The Open-Source Drug Discovery (OSDD), which is dedicated to
discovering treatments for diseases that plague the developing
world, surprised many when more than 400 of its volunteer
researchers reannotated the tuberculosis bacterium genome, wiki
style, in just 4 months—record time for such an endeavor
Source: Margie Patlak. Open-Source Science Makes Headway
J Natl Cancer Inst. 2010 Aug 18;102(16):1221-3
Nagasuma Chandra,
Indian Institute of Science, Bangalore
OSDD SInCRe
An Open Source Integrated Computational Resource for the Analysis of the
Structural Interactome to predict Off-Site Interactions of Drug Candidates
Nagasuma Chandra, R. Sowdhamini, N. Srinivasan & Sir Tom Blundell
Ongoing: Cheminformatics
Community of About 400
PubChem
ChEMBL
DrugBank
HT Virtual
screening
Curated molecule
datasets
Cheminformatics
Models
Data Mining
and Analysis
Other Active Communities:
•OSDD Women Scientists Forum
•OSDD Junior Scientists Forum
Experimental
Assays
Cheminformatics – Large Scale
Data Analysis
Data
Processing
Size
increases
Software
Output
Heap Size
issues
Power MV
and WEKA
Cheminformatics – Large Scale Data
Analysis
• Accessing large data files from online repository such as
Pub Chem.
• Basic computational resources – 4Gb RAM
Pub Chem
1.04Pb
Database
Max
bandwidth
- 1-4 Mbps
4Gb RAM
Local
Systems
C-DAC’s Garuda Grid –
Indian Grid Computing Initiative
• C-DAC is R&D organization under Ministry
of Communication & Information
Technology, India
• C-DAC’s Garuda Grid is targeted at
providing a facility for the scientific
community, which would enable them to
seamlessly access the distributed
resources.
• Compute Power of GARUDA: ~ 70TFs
(6000 CPUs)
• Currently there are 55 Garuda Partners
• Has NKN (National Knowledge Network)
connectivity at 10Gbps
Garuda Usage by OSDD:
Job Accounting
OSDD - Linking Institutions and Competencies
Hits identified
through virtual
screening are
synthesized
and tested for
enzyme assay
GlmU predicted
as potential
drug target
IIT Kanpur:
Crystal Structure
of GlmU
Synthesis of Molecules:
IICB Kolkota and Univ.
of Saurashtra, Gujrat
45 Hits Selected
for Screening
Feedback loop
to improve
inhibitors
Screening at
NII
Creation of Library of Drug Like Compounds
Filtering Criteria for Pruning 50,000 compounds
from Chembridge Database
 Molecular Weight < 400
 Remove molecules other than H,C,N,O,F,S,P,Cl,Br, or I
 ADME properties (Principle descriptors & Prediction of
properties) based on 1712 drugs.
 Shrinking the CLogP window between 1.5 & 5
A physical compound library of drug like
compounds. (20,000 compounds)
Whole cell screening
OSDD Open Chemistry
Led by CSIR- CDRI, India’s National Drug
Research Laboratory
OSDD Open Chemistry
 Challenge
Need novel molecules for screening against
TB/Malaria
 OSDD Approach
 Open source small molecule synthesis involving 40
chemistry departments from colleges across India
 Web based collaboration and discussion
OSDD Team at work in SASTRA
Project implementation through
students selected via pan India
online primer designing exercise
More than 30
genes cloned in
less than 3 months
POC for downstream experiments
• Fifteen undergraduate students were given hands on
training in various Molecular biology techniques
• So far, 11 genes have been cloned in pGEM-T easy
vector
• 20 have been cloned in pET28 a/b/c and expressed
(Verified by SDS –PAGE)
Status: OSDD Projects
Drug Target
Identification
Chemical
Synthesis/
library
Virtual
Screening
18
Screening/ Hit
identification
Hit to Lead
Other projects aim to
develop tools,
databases and
repositories for the
OSDD community
19
9
6
2
OSDD Publications
1) Bhardwaj A, et al. Open Source Drug Discovery- a new paradigm of collaborative
research in Tuberculosis drug development. Tuberculosis, 2011 (in press)
2) Bhardwaj A, et al. Collaborative Tools to Accelerate Neglected Disease Research: the
Open Source Drug Discovery Model [Book Chapter]in Collaborative Computational
Technologies for Biomedical Research, Wiley and Sons, May 2011.
3) Bhat AG, et al. Modeling metabolic adjustment in Mycobacterium tuberculosis upon
treatment with Isoniazid. Systems and Synthetic Biology. 2011 Volume 4, Number 4,
299-309.
4) Sharma S, et al. Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump
of Mycobacterium tuberculosis. J Antimicrob Chemother. 2010 Aug;65(8):1694-701.
5) Mishra NK, et al. Prediction of cytochrome P450 isoform responsible for metabolizing
a drug molecule. BMC Pharmacol. 2010 Jul 16; 10:8.
6) Mathew R, et al. Inhibition of mycobacterial growth by plumbagin derivatives. Chem
Biol Drug Des. 2010 Jul 76(1); 34-42.
7) Garg A, et al. KiDoQ: using docking based energy scores to developligand based
model for predicting antibacterials. BMC Bioinformatics. 2010 Mar 11;11:125.
8) Bhardwaj A, et al. Open Source Drug Discovery Consortium, TBrowse: an Integrative
Genomics Map of Mycobacterium tuberculosis. Tuberculosis (Edinb). 2009 Sep;
89(5):386-7.
9) Bhardwaj A, et al . Open source drug discovery: a global collaborative drug discovery
model for tuberculosis. Science and culture, January-February, 2011, vol. 77, nos. 1–2,
22-26.
Geek Nation: How Indian Science Is Taking Over The
World
“.. explores the reason why the
government of the most religious
country on earth has put its faith in
science and technology..”
Author, Angela
Saini
Responses from the OSDD Community
•I have had a thrilling experience with OSDD for the past 2 years and now I am
ready to pursue my PHD at Indiana University
Abhik Seal, SBI Employee, Calcutta
•I can access the CDAC supercomputing facility The Garuda Grid sitting at
any place from anywhere in the world.
Rajdeep Poddar, Bio IT Application Specialist
•OSDD is a boon to me, giving me a platform to research when I was at cross
roads regarding career ,family and research
Swati Gandhi ,Baroda, Gujrat
•It has been a dream come true and a great learning experience after
becoming a part of OSDD
Dr Preetha Anil, SIAS, Kerala
•I still remember what I said to myself on second day of OSDD conference
looking into the mirror... “Is this the Shamsudheen from that remote
village?????....!!!!!”
Shamsudheen K.V ,IGIB
Together we can …
.. and we should !
http://www.osdd.net
http://c2d.osdd.net
http://sysborg2.osdd.net
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