Team India Consortium with Global Partnership

Council of Scientific and Industrial Research INDIA

A CSIR-led initiative for affordable healthcare to the developing world

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 personevery 20 seconds

1.7 Million people every year

In IndiaNearly 1000 people every day

Two peopleevery 3 minutes

TB Kills

Image Credits:  Teseum/Flickr

More than 2 billion people (~1/3 of world population) is affected with the tubercle bacilli

Deaths due to Tuberculosis in 2008 Source: GlobalHealthFacts.org

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 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

Potential hit Lead Optimization

DRUG TARGET BASED(18 Drug Targets)

LIGAND BASED(Pubchem Bioassay Data/New inhibitors/)

NATURAL PRODUCT BASED (135 Phytomolecules )

Community peer reviewOpen Funding Review

Assembly line for drug discovery

I Biological Repository

i. Open access clinical strains repositoryii. Open access clone repositoryiii. Open access protein repository

II Chemical Repositoryi. Open access small molecule repository

III Open Screening Facility i. Submit your compounds for anti-tuberculosis

screening

OSDD Open Access Resources

Bhardwaj et al. Tuberculosis (Edinb). 2009 Sep;89(5):386-7

http://tbrowse.osdd.net

Computational Resources developed with Community participation

Bhardwaj et al. 2011 John Wiley & Sons, Inc.

Mtb essen\tial genes database

TrapTBMtb drug targets database

Chembio ToolkitWorkflow engine with federated resources

AmPhyDBAntimycobacterial Phytomolecule Database

http://sysborg2.osdd.net

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

Drug Targets (TDR/Plos/TDI)

Operon predictions (DOOR/VIMSS/Rutherford)

* 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

Drug Targets (TDR/Plos/TDI)

Operon predictions (DOOR/VIMSS/Rutherford)

More than 100 datasets

encompassing a million data points

AnshuBhardwaj

DeekshaBhartiya

NitinKumar

VinodScaria

OpenLabNoteBook on SysBorgTBhttp://sysborgtb.osdd.net/bin/view/OpenLabNotebook/TBMapDataset

Publication in Tuberculosis 2009

Deeksha Bhartiya Nitin Kumar

Literature

Annotation Tools

Genomic Databases

Curated Annotations

Raw Annotations

OSDD C2DCommunity

800+ Student

Researchers

Collaborative Curation

Pathway/Interactome | Gene Ontology | Protein Structure/Fold | Glycomics| Immunome

Pathway/Interactome | Gene Ontology | Protein Structure/Fold | Glycomics| Immunome

The “Connect to Decode” Programme

“Given enough eyeballs, all bugs are shallow”

Errors are marked by the Community for Correction

Errors are corrected by the Community

-Linus Torvalds

Errors are Discussed by the Community

Literature

Annotation Tools

Genomic Databases

Curated Annotations

Raw Annotations

Community of >800 student researchers

Collaborative Curation

Innovative Crowd Sourcing Model for Mtb Systems Biology

Generated the largest Interactome & Metabolic Map of Mtb

87% of Mtb genome annotated

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&DRepower 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 HeadwayJ Natl Cancer Inst. 2010 Aug 18;102(16):1221-3

Nagasuma Chandra, Indian Institute of Science, Bangalore

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

OSDD SInCRe

Ongoing: Cheminformatics

Curated molecule datasets

Curated molecule datasets

Cheminformatics Models

Cheminformatics Models

Data Mining and AnalysisData Mining and Analysis

HT Virtual screeningHT Virtual screening

PubChemPubChem

ChEMBL ChEMBL

DrugBankDrugBank

Experimental Assays

Experimental Assays

Community of About 400

Other Active Communities:•OSDD Women Scientists Forum•OSDD Junior Scientists Forum

Software

Processing

Power MV and WEKAPower MV and WEKA

Output

Size increases

Size increasesHeap Size

issuesHeap Size

issues

Data

Cheminformatics – Large Scale Data Analysis

Cheminformatics – Large Scale Data Analysis

• Accessing large data files from online repository such as Pub Chem.

• Basic computational resources – 4Gb RAM

Database

Local Systems

Pub ChemPub Chem

4Gb RAM4Gb RAM

Max bandwidth - 1-4 Mbps

Max bandwidth - 1-4 Mbps

1.04Pb

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

45 Hits Selected for Screening

OSDD - Linking Institutions and Competencies

Hits identified through virtual screening are synthesized and tested for enzyme assay

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)

Creation of Library of Drug Like Compounds

Filtering Criteria for Pruning 50,000 compounds from Chembridge Database

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

• 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)

POC for downstream experiments

18

19

9

6

2

Status: OSDD Projects

Other projects aim to develop tools, databases and repositories for the OSDD community

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.

OSDD Publications

Author, Angela Saini

Geek Nation: How Indian Science Is Taking Over The World

“..a journey to meet the inventors,

engineers and young scientists behind this

nation built not on conquest, oil or minerals,

but on the scientific ingenuity of its people..”

“.. explores the reason why the government of the most religious country on earth has put its faith in science and technology..”

“.. explores the reason why the government of the most religious country on earth has put its faith in science and technology..”

“..The West may think India is still in the gutter, but it is looking at the stars..”

“..The West may think India is still in the gutter, but it is looking at the stars..”

•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

Responses from the OSDD Community

Together we can ….. and we should !

Matt Smadley | Flickr.com

http://www.osdd.nethttp://c2d.osdd.net

http://sysborg2.osdd.net