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Osp 1st sep2015 OSDD

OSDD by Geetha Vani Rayasam

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Osp 1st sep2015 OSDD

  1. 1. Open Source Drug Discovery OSDD Geetha Vani Rayasam Principal Scientist
  2. 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, 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. 3. OSDD Strategy To Drug Discovery & Development
  4. 4. Community Peer Review Open Funding Review
  5. 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. 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. 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. 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. 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. 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. 11. OSDD Open Chemistry
  12. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 23. Suggestions for OSP Vision & Mission 5 years Outputs Outcomes 10 years Outputs Outcomes Break Up into Yearly Actionable Milestones/Deliverables
  24. 24. Together we can … .. and we should ! Matt Smadley | Email: 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…….