OSDD by Geetha Vani Rayasam

1. Open Source Drug Discovery
OSDD
www.osdd.net
Geetha Vani Rayasam
Principal Scientist

2. The Open Innovation Model : OSDD strategy
• Porous-walled funnel facilitates free flow of ideas / projects
• Bring in more eyeballs to look at the inside
• Enables Redundancies and Parallelization
Fuzzy Front-End Research DevelopmentInputs
INTEGRATED
OSDD PROJECT
Inputs
Platforms driving the
process
Technology
Hits / Lead Molecules
Image Source: Clorox, Andy Gilinkski,
www.imaginatik.com
OSDD
OSDD
INDIVIDUAL PIs
IDEAS
Marrying The TWO CULTURES
- Academic
- Delivery focused
- OSDD THE FACILITATOR
OSDD the leader
- Expertise
- Discovery Platforms
GLOBALISING
THE EFFORT
New Combination
GATB

3. OSDD Strategy To Drug Discovery & Development

4. Community Peer Review
Open Funding Review

5. Open
Peer
Review
(4 weeks)
Scientific
Expert
Review
(4 weeks)
Budget
Review
(2 weeks)
Process of Project Proposal Review, Approval and
Implementation
Principal Investigator: Posts a project proposal on Sysborg
Periodic Monitoring & 6 monthly Review
Scientific Inputs from Science Support Group

6. OSDD: Coordination of Activities
Bottom Up
Top Down
 Individual Driven
 Volunteer contributions
 Progression of target based & ligand
based approaches
 Contribution of resources and skills
Community Developed Projects
 Crowd sourcing for solving challenges
(genome annotation for systems level
understanding)
 Streamlining processes & resources
(repositories/computational resources)
 Focused effort to targeted deliverables
(CROs & Academic Collaborations)
Centrally Coordinated Projects

7. Literature
Annotation
Tools
Genomic
Databases
Curated
Annotations
Raw
Annotations
OSDD C2D
Community
800+ Student
Researchers
Collaborative
Curation
Pathway/Interactome | Gene Ontology | Protein
Structure/Fold | Glycomics| Immunome
The “Connect to Decode” Program

8. Crowdsourcing
MPDSTB
Phase I
2009
Phase II
2010
Phase II
2011
Phase III
2013-14
Chem-
informatics
Phase II
2012-13
Genome Annotation for Drug
Target Identification through
Systems Level Analysis
Cloning of predicted targets &
cheminformatics to predict
potential inhibitors
Identify target-specific filters;
Establish Molecular Property
Diagnostic Suite

9. Current status
 No. of PIs: 84 (88 projects)
 Current library strength: 10000
 Compounds screened: 8500
 Scaffolds prioritized: 11
 Compounds screened against malarial
parasite
• 16 primary hits
Chemically Diverse Compounds
N
N
O
O
N
N
O
N
N
N
N
N
N
Cl
N
N
OH
O
H2N
NCL: Carbohydrate Chemistry
CLRI: Heterocyclic Chemistry
IICT: Peptide & Natural Product Chemistry
NIIST: Natural Product Chemistry
NEIST: Heterocyclic Chemistry
IIIM: Medicinal chemistry
CDRI: Medicinal and Scale up Chemistry
Distribution of Chemistry PIs across India
Cl
O
S
N
N
N
OSDD’s Chemistry approach for TB drug discovery

10. Figure 2. General structures of proposed molecules 7, 8 and 9
N
N S
O
R1
R2
R
R=Heterocycl, alkyl, aryl, alkenyl,
OH, OR3
, COOR4
, CONR5
R6
etc,
R1
, R2
= H, subst alkyl, subst aryl
N
N S
O
X
R1
R2
N
R= subst alkyl, subst aryl,
CH2OH, CH2OR3
, COOR4
etc,
R1
, R2
= H, subst alkyl, subst aryl
X= (CH2)n
N N
R
R= subst alkyl, subst aryl,
CH2OH, CH2OR3
, COOR4
etc,
R1
, R2
= H, subst alkyl, subst aryl
X= (CH2)n
N
N S
O
X
R1
R2
N
N
N
R
6
7 8
Figure 3. General structures of proposed molecules 9 and 10
N
H
S
R1
R2
R= CN, COOR4, CONR5R6 etc,
R1
, R2
= H, subst alkyl, subst aryl
R3
= subst alkyl, subst aryl
R,R', R3= H, subst alkyl, subst aryl
R1
, R2
= H, subst alkyl, subst aryl
R4= subst alkyl, subst aryl
9 10
R
R3
O
N S
R1
R2
N
N N
R4
R3
R'RN
O
Project Proposal (Dr. Borate, NCL)
i. Prioritize thienopyrimidines
ii. thiourea, thiocarbamate, hydrazide, pyridyl amine, phenyl
amine etc may be avoided from the point of toxicity
iii. Dicyanoanilines need to be removed
iv. R, R1, R2 may be independently chosen from aryl, heteroaryl,
CONH2, SO2NHR’, OH and a chain containing OH, OR and NHR
groups. Restrict to only one or two aromatic/heteroaromatic
rings
1 32 4 5
Compounds synthesized
N
N S
R
O
R1
Project Formulation
i. This is an example describes how projects are formulated
ii. Scientific inputs are provided to all chemistry projects

11. OSDD Open Chemistry

12. Bridging the Gap in Drug Discovery: CDRI-830 Project
Around 150
analogues,
MIC on M. tb.
Trisubstituted methanes
(CDRI-830)
H, Alkoxy, S-alkyl,
F, Cl, in o, m and
p positions. P-
MeO and p-F are
the most potent.
Phenyl, naphthyl,
pyridyl, indolyl,
pyrrolys
Only naphthyl is better
tolerated
Many open chain
and cyclic groups.
Only diisopropyl is
better tolerated.
No substitutions
tried on ring B
New CDRI 830 Fragment OSDD-29
Identified
~ 300 compounds Designed and
synthesized by OSDD and Jubilant
SAR
SAR
Several potent ‘hits’ identified
(<1 ug/ml)

13. OSDD Model of Translating Academic Research into Drug
Discovery Projects
Identify
Potential
Academic
Projects
Work with the
PI in building
the discovery
project
Bring in additional
complementary academic
partners
Strong Drug
Discovery Project
with clear
deliverables and
time linesContract Research
Organizations to fills the
gaps in drug discovery
OSDD Drug Discovery
Experts Inputs

14. Translating Academic Research into Drug Discovery Dap A/B Project
0
0.2
0.4
0.6
0.8
0 5 10 15 20
Absorbanceat334nm
Time in Min.
Low throughput
Assay
DapA/DapB:
Cloning/expression
/purification
Random Screening of
3500 compounds
IC50s of hundreds of
compounds
ChemoInformatics
Identify new
libraries
Validate the ‘hits’
Secondary ‘binding assays’
Orthogonal assays: HPLC/LC-MS
0
0.1
0.2
0.3
0.4
0.5
0.6
0 10 20 30 40 50 60
OD334nM
Time in mins
High Throughput Assay
Structure-based Strategy
Project Driven By OSDD
• Intellectual input
• Bringing in Partners: Anthem
0%
20%
40%
60%
80%
0 200 400 600
%Inhibition
Compound (µM)
0-10
0-20
0-30
0-40
0-50
0-60
a Keto Pimelate
an inhibitor of DapA/B

15. OSDD-TB Alliance Phase IIb Clinical Trial
In MDR Tuberculosis Patients
To evaluate the anti-mycobacterial activity, safety, tolerability and
pharmcokinetics of drugs/regimens under evaluation
• Trial Center: LRS Institute of Tuberculosis (a tertiary care hospital)
• Trial Size: ~80 patients in each arm
Recruitment has been initiated
Trial data to be made open without comprising patient confidentiality
Pa+ Cat IV regimen 2 months of treatment
Cat IV regimen
Pa-M-Z
Cat IV treatment
Pa = PA-824;
M = moxifloxacin;
Z = pyrazinamide
Hospitalization

16. •Central storage and distribution
center (CDRI and MolBank @ IICT)
•Open database (OSDD ChemDesign)
•Target validation with knockout &
knockdown in M.smeg and M.tb
and clinical strains (Premas Biotech)
•Cloning, expression & purification of
targets. (Sastra University, CSIR labs,
and Anthem)
•Assay development and
optimization (Labs and Anthem)
•High throughput biochemical
screening (Anthem)
•Whole-cell screening
M.smeg (IICT)
M.tb (CDRI, IIIM, IGIB & Premas
Biotech)
Malaria (CDRI)
•Toxicity in mammalian cells (IICT)
•Generation of compound-resistant
mutants (CDRI)
•Whole genome sequencing (IGIB
and CROs)
Platforms Currently Established
Mechanism
of Action
ScreeningBiology
Compound
Management

17. Screening Hit to Lead
Whole Cell based Target based
• Screening of 20,000 drug like compounds:
analysis and prioritize new scaffolds (CSIR-
IIIM)
• Screening of 30,000 compounds, in replicating
and non replicating Mtb (CSIR-IIIM)
• Screening of 30,000 compounds (CSIR-CDRI)
• Screening of 10,000 compounds (CSIR-IICT)
 Directed Chemistry Synthesis at CSIR
Labs: 60 projects
IICT/NCL/NIIST/NEIST/CLRI
• OSDDChem: > 20 projects from various
institutes and universities; screening in parallel
against TB and malaria (CSIR-CDRI)
• Plant derived anti-Infective library (1000) of
pure compounds (Premas Biotech)
• Identification of anti-mycobacterial molecules
from Actinomycetes (RGCB)
• GlmU: Development of inhibitors through
structure based drug design (NII/BITS-Hyd/IIT-K)
• Dap A/B: Identification of new inhibitors (CSIR-
IGIB/Anthem Biosciences)
• Structure-activity relationship study of NAD
Dependent LigA inhibitors (CSIR-CDRI)
• Disruption of Sigma Factors-RNA polymerase
interaction to target Mtb (OSDD Unit/IISc)
• Investigation on bioactive molecules inhibiting
betalactamases and MAP of Mtb (CSIR-NIIST)
• Identification of inhibitors targeting Mur pathway
(ANDC)
• The role of dos regulon proteins of Mtb in
persistence (Univ of Hyderabad)
• Phage based therapy for TB (Ganagen)
• Ribosome Biogenesis (IIT-K)
• Inhibitors of Type 7 secretion (OSDD & Univ of
Umea, Sweden)
• CDRI-SOO6-830: SAR
analysis, initial PK, MOA
studies (CSIR-CDRI /
Jubilant Chemsys)
• LAMS (CSIR-IGIB /CSIR-
NCL/Jubilant Chemsys):
Identifying new
chemotypes & single target
vs. multi target
• Optimization of ‘hits’ from
whole cell based screening
for TB (CSIR labs &
Jubilant Chemsys)
OSDD Discovery Portfolio for TB
Other Projects: Resources/New Concepts/Diagnostics/Pharmacogenomics/Mtb
genome sequencing
More than 180 PIs from over 100 institutions contributing to the portfolio

18.  Long Term Commitment and Sustained Support
to the Philosophy and Program
• patents/royalty/pricing/licensing
 Risk taking ability
 Partnering with Industry
Key Learning in Implementation of Drug
Discovery Program in an Open Source Setting
Slide 1 of 4

19. Key Learning in Implementation of Drug
Discovery Program in an Open Source Setting
Slide 2 of 4
 Working with compounds/regimens developed
outside India
 Obtaining regulatory clearances for clinical
trials
 Incorporation of approved drugs into the
national program

20. Slide 3 of 4
Key Learning in Implementation of Drug
Discovery Program in an Open Source Setting
 Leadership and Implementing Team
 Building trust and confidence in the model, in sharing
data and in the executing team
 What drives the collaborations?? Academics..
• Provide value to the contributors
 Transparent decision making
 Transparent credit sharing

21.  Engaging multiple national and international stakeholders and
financing them
 Faster and efficient delivery of funds
 Hiring and retaining technical experts from Industry
 Funding Crowd Sourcing activities
 Engaging and delivery from CROs
Key Learning in Implementation of Drug Discovery
Program in an Open Source Setting
Slide 4 of 4

22. Synergy Between Different Players
Affordable
Drugs for
Neglected
Diseases
PDPs
Clinical Development
Government
Agencies
Discovery
Clinical Trials &
Implementation
Not for Profit
Pre-clinical
Development
Industry Collaboration
Crowd Sourcing
Proof of Concept to be established on Success for Open Source Philosophy in
Affordability of drugs and Increased rates of Success
Complement Not Compete

23. Suggestions for OSP
Vision &
Mission
5 years
Outputs
Outcomes
10 years
Outputs
Outcomes
Break Up into Yearly Actionable Milestones/Deliverables

24. Together we can …
.. and we should !
Matt Smadley | Flickr.com
http://www.osdd.net
http://c2d.osdd.net
http://sysborg2.osdd.net
http://crdd.osdd.net/osddchem/index.html
Email: info@osdd.net
Dr Sarala Balachandran: Project Director & Clinical Trials
Dr Anshu Bhardwaj: Predictive Sciences & Crowd Sourcing Expert
Prof SK Brahmachari
Dr T Balganesh
Zakir Thomas
Dr Haridas Rode
Dr B. Ugarkar
Dr Jaleel
Principal Investigators, Consultants, Students
CROs, Collaborators, OSDD Community…….