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: info@osdd.net

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…….