Date post: | 17-Feb-2017 |
Category: |
Health & Medicine |
Upload: | alina-grenier-arellano |
View: | 161 times |
Download: | 0 times |
Open Source Drug Discovery OSDD
www.osdd.net
Geetha Vani RayasamPrincipal Scientist
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
INTEGRATEDOSDD PROJECT
Inputs
Platforms driving the process
Technology
Hits / Lead Molecules
Image Source: Clorox, Andy Gilinkski, www.imaginatik.com
OSDD
OSDD
INDIVIDUAL PIsIDEAS
Marrying The TWO CULTURES- Academic- Delivery focused- OSDD THE FACILITATOR
OSDD the leader- Expertise- Discovery Platforms
GLOBALISING THE EFFORT
New CombinationGATB
OSDD Strategy To Drug Discovery & Development
Community Peer ReviewOpen Funding Review
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 ReviewScientific Inputs from Science Support Group
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
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
The “Connect to Decode” Program
Crowdsourcing
MPDSTB
Phase I2009
Phase II2010
Phase II2011
Phase III2013-14
Chem-informatics
Phase II2012-13
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
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
NCL: Carbohydrate ChemistryCLRI: Heterocyclic ChemistryIICT: Peptide & Natural Product ChemistryNIIST: Natural Product ChemistryNEIST: Heterocyclic ChemistryIIIM: Medicinal chemistryCDRI: Medicinal and Scale up Chemistry
Distribution of Chemistry PIs across India
OSDD’s Chemistry approach for TB drug discovery
Project Proposal (Dr. Borate, NCL)i. Prioritize thienopyrimidinesii. thiourea, thiocarbamate, hydrazide, pyridyl amine, phenyl
amine etc may be avoided from the point of toxicityiii. 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
Project Formulation
i. This is an example describes how projects are formulatedii. Scientific inputs are provided to all chemistry projects
OSDD Open Chemistry
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, pyrrolysOnly naphthyl is better tolerated
Many open chain and cyclic groups. Only diisopropyl is better tolerated.
No substitutions tried on ring B
S
ON
O
Log P: 6.62tPSA: 21.7
CLogP: 6.9058pKa: 9.445
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)
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
Translating Academic Research into Drug Discovery Dap A/B Project
0 2 4 6 8 10 12 14 16 18 200
0.10.20.30.40.50.60.70.8
Time in Min.
Abs
orba
nce
at 3
34nm
Low throughputAssay
DapA/DapB: Cloning/expression/purification
Random Screening of 3500 compounds
IC50s of hundreds of compounds
ChemoInformaticsIdentify 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
Time in mins
OD
334
nM
High Throughput Assay
Structure-based Strategy
Project Driven By OSDD• Intellectual input • Bringing in Partners: Anthem
0 100 200 300 400 500 6000%
20%
40%
60%
80%
0-100-200-300-400-500-60
Compound (µM)
% In
hibi
tion
a Keto Pimelatean inhibitor of DapA/B
OSDD-TB Alliance Phase IIb Clinical TrialIn 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 initiatedTrial 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
•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
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
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
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
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
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
Synergy Between Different Players
Affordable Drugs for Neglected Diseases
PDPs Clinical Development
Government AgenciesDiscovery
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
Suggestions for OSP
Vision & Mission
5 yearsOutputs Outcomes
10 yearsOutputsOutcomes
Break Up into Yearly Actionable Milestones/Deliverables
Together we can ….. and we should !
Matt Smadley | Flickr.com
http://www.osdd.nethttp://c2d.osdd.net
http://sysborg2.osdd.nethttp://crdd.osdd.net/osddchem/index.html
Email: [email protected]
Dr Sarala Balachandran: Project Director & Clinical TrialsDr Anshu Bhardwaj: Predictive Sciences & Crowd Sourcing Expert
Prof SK BrahmachariDr T BalganeshZakir ThomasDr Haridas RodeDr B. UgarkarDr Jaleel
Principal Investigators, Consultants, StudentsCROs, Collaborators, OSDD Community…….