Steve Brudz

Manager, Software Engineering Chemical Biology Platform

The Evolution of the Broad Chemical Biology Informatics Platform From Screening to Lead Optimization

Faculty: Nine Core Members in Broad buildings

155 Associate Members: Faculty with labs at MIT, Harvard, Whitehead, or affiliated hospitals

An Experiment in Philanthropy and Organization

2003 – 2006: $200M “venture philanthropy” investment by Eli and Edythe Broad to accelerate the transformation of medicine

2008: The Broads announced an endowment of $400 million making the Institute a permanent nonprofit organization

Unique Collaborative Structure Enables the Broad Mission

Broad Platforms

The Broad's Scientific platforms are made up of professional scientists with the expertise and organization to carry out major projects that cannot be done within a single laboratory

Imaging

RNAi

Chemical Biology/ NovelTherapeutics

Proteomics

Genetic Analysis

Genome Sequencing

Biological Samples

Broad Programs

The Broad's Scientific programs bring together research groups with a shared commitment to important biomedical challenges

Infectious Disease

Chemical Biology

Medical & Popul’n Genetics

Psychiatric Disease

Stanley Center

Metabolic Disease

Cell Circuits

Genome Biology

Cancer

Computational Biology

Advances needed to explore human biology systematically:

•  To innovate in fundamental chemistry: Developing next-generation synthetic chemistry that reaches ‘undruggable’ targets or processes.

•  To bring complex biology to small-molecule science: Screening in physiologically relevant conditions.

•  To understand how small molecules affect disease: Determining the proteins that small-molecule modulators bind in cells.

From Opportunistic to Disciplined: Modulating Challenging Targets

1997 2002 2004 2006 2008 2012 2010 2000

ActivityBase PubChem 2.0 1.0

Broad Institute Chemical Biology Platform Early DOS Concepts

NCI Initiative for Chemical Genetics

Broad Institute of Harvard & MIT

Design DOS library

Design screening system

Automation; MLPCN comprehensive center; 1st DOS compounds

The Broad Institute (7/2009)

150K DOS Library Y3/Y4 MLPCN

Screening, Hits Structural Diversity, Screening, Hit to Probe High Quality Probes Lead Optimization

  Academic Screening Center for collaborative high throughput screening through hit validation

–  DOS Chemistry Library Production –  HTS screening on 100,000 compound set

  Comprehensive Center for the Molecular Libraries Probe Production Centers Network (MLPCN)

–  HTS screening on 300,000 compound set –  Confirmation and dose assays –  Follow-up medicinal chemistry

  Goal to find novel probes and therapeutics

Screening Collection

MLPCN (~324K)

New code Collection name # of compounds COMB Commercially available 296,780 BIOA Bioactives 442

STRD Non-commercial stereochemically diverse 14,801

NATP Natural products - purified 1,472 GPCR G protein-coupled receptor biased 3,880 IONC Ion channel targeted 1,956 KINA Kinase biased 3,892 NUCR Nuclear receptor targeted 152 PROT Protease targeted 684

324,059

Broad (~102K)

Code Collection name # of compounds CBLI DOS 61,004

CHRM Chromatin biased 2,327 BIOA Bioactives 4,920

STRD Non-commercial stereochemically diverse 2,115

NATP Natural products - purified 1,291 KINA Kinase biased 12,119

COMA Commercial - Forma 1,133 COMB Commercial - other 12,278 GPCR G protein-coupled receptor biased 5,000

102,187

MW vs. ALogP

Molecular Weight

ALo

gP

COMA CBLI STRD NATP

T. E. Nielsen, S. L. Schreiber, Angew Chem Int Ed Engl 47, 48 (2008)

•  Objective: Generate novel small molecular probes •  Assays sourced from the scientific community

-  “Fast-track” (specific objective in NIH grant e.g. R01) -  “HTS-ready” (R03) -  Assay development (R01)

•  Perform HTS, secondary screens and medicinal chemistry •  Data shared globally through PubChem, published probe reports

7

MLPCN: Molecular Libraries Probe Production Centers Network

https://mli.nih.gov/mli

CBIP v1.0 – Transactional, Data Producer focused

Reagent Inventory

Cellario

Library Design Chemistry ELN

CBIP Library Production

CBIP Cleavage & Formatting

CBIP Compound Management

CBIP Analytical Viewer

HTS/Data Analysis

Analytical Data CBIP Screening LIMS

Walk-up Instruments

Purchasing

Screening Data Warehouse

Data Visualization & Analysis

Chemistry/Cheminformatics Analytical Chemistry

Compound Management HTS/Data analysis

Automation Integration

CBIP Compound Registration

CBIP v1.0 – March 2010 – High Level Architecture

800K samples, 450K structures, 30M observations

Challenges:   Compound Registration   PubChem Data Submission   Results Data Querying

ChemAxon products:   Marvin   JChem API   Standardizer   Oracle Cartridge   Pipeline Pilot Plug-in   Chemical Terms   Instant JChem

CBIP v1.5 – Sept. 2011 – High Level Architecture

1.8M samples, 520K structures, 77M observations

  Compound Registration integrated with ELN   PubChem Data Submission automated via in-house tool   Hit calling and Cherry Pick workflows via TIBCO Spotfire   Improved SAR via Seurat and SSAR Visualization Tool

SD File Mol File

Conversion to smiles

Standardization

Desalting

Calculate chemical properties

Pipeline Pilot canonical tautomer

Unspecified chirality flag

Structure registration and Broad Id assignment

Compound Registration

Automated single and batch compound registration from CambridgeSoft ELN via Registration Service

  Marvin for editing and rendering   Standardizer for Standardization & Desalting   JChem API for properties calculation (mass and chirality detection)

Cherry Pick Workflow in TIBCO Spotfire

Scientists choose compounds for follow up using activity, structure, and chemical properties

Examine Hit Calling Results

Filter out undesirable

substructures

Filter by structure properties

Find related compounds of

interest

Cherry Pick compounds for follow up

Cherry Pick Workflow in TIBCO Spotfire

Compound collection is pre-annotated by substructure in database to improve performance

Examine Hit Calling Results

Filter out undesirable

substructures

Filter by structure properties

Find related compounds of

interest

Cherry Pick compounds for follow up

Cherry Pick Workflow in TIBCO Spotfire

Chemical properties are pre-computed using ChemAxon’s Chemical Terms during ETL of compounds into database

Examine Hit Calling Results

Filter out undesirable

substructures

Filter by structure properties

Find related compounds of

interest

Cherry Pick compounds for follow up

Cherry Pick Workflow in TIBCO Spotfire

Similarity search via the Jchem cartridge is used to find additional compounds of interest

Examine Hit Calling Results

Filter out undesirable

substructures

Filter by structure properties

Find related compounds of

interest

Cherry Pick compounds for follow up

Nielsen T.E.; Schreiber, S.L. Angew. Chem. Int. Ed. 2008, 47,48-56

What is Diversity-Oriented Synthesis?

DOS is a strategy for efficient synthesis of collections of small molecules having skeletal and stereochemical diversity with defined coordinates in chemical space

SSAR Visualization Tool

2 out of 8 stereoisomers

active

RSS SRR RRR SSS

RSR SRS RRS SSR

Tools for Stereo/structure –activity analysis

Tool uses file for data, structures from database, Jchem API for rendering and sorting of building blocks

SSAR Visualization Tool

>90%

75-90%

50-75%

<50%

R1

R2

QC Analysis of DOS Libraries

Repurposing Stereo/structure –activity analysis tools

CBIP v2.0+ – 2012/2013 – High Level Architecture

Resolve Current Challenges:   Research Data Management   Improve Results Data Querying   Dimensional Data Model   Modularize transactional CBIP   Transition to Groovy & Grails

DataProducers

DataConsumers

Multi-dimensional Querying & Reporting

Multi-dimensional Data AnalysisSSAR

Visualization Tool

Accelrys Pipeline Pilot

TIBCO Spotfire Schrodinger Seurat

Results Dimensional Warehouse

OtherData

ContentUnstructured

Data/Files

Transactional/Operational

Results DBPubChem

Submission Tool

Data Dictionary (MDM)

Catalog of Assay Protocols

Compound Registration

DOS Chemistry

AnalyticalADME

Compound Management

CambridgeSoft ELN NuGenesis SDMS

Screening, Instrument Automation,Confirmation & LTS Assays

Genedata Assay

Analyzer

Biology-specific ELN

Accelrys Pipeline Pilot

Compound Ordering

Genedata Condoseo LTS

SSAR Visualization

Tool

Accelrys Pipeline Pilot

TIBCO Spotfire Schrodinger Seurat

Lessons Learned

•  It’s great to have a toolkit! –  We’ve successfully integrated many ChemAxon tools across many

systems –  The Java API is extensive and well-documented

•  ChemAxon’s support is excellent –  Forum is a great resource –  Frequent releases are nice…

•  …but we can’t keep up –  Testing cartridge upgrades is expensive –  So many integration points require extensive testing for every

upgrade

•  We would love to have Grails plug-ins from ChemAxon –  Integration of Molecule and Reaction data types into GORM –  Easy integration of Marvin into GSPs

Broad Chemical Biology Platform

Cheminformatics Lakshmi Akella Carol Mulrooney

Informatics

Platform Director Mike Foley Program Director Stuart Schreiber

Screening Michelle Palmer

Medicinal Chemistry Benito Munoz Siva Dandapani Rich Heidebrecht

Funding: Broad, NIH (MLPCN, CMLD, GBDD, CTD2)

DOS Lisa Marcaurelle Jeremy Duvall Eamon Comer Sarathy Kesavan Jason Lowe Baudoin Gerard

Mary Pat Happ Dennis Moccia Gil Walzer Karen Emmith Evan Mulligan David Lahr Michael Quintin

Steve Brudz Daniel Durkin Jacob Asiedu Xiaorong Xiang Jeri Levine Peter Chen Ben Alexander

Novel Therapeutics Christina Scherer

Lead Discovery Joshua Bittker Assay Development Jose Perez Analytical Chemistry Stephen Johnston

Outreach Lab Nicola Tolliday

HTS James Spoonamore

Automation Gavin McKeown Tom Hasaka

Enzymology Yan-Ling Zhang

Compound Management John McGrath

Project Management Patti Aha

Stanley Center Ed Holson Florence Wagner

Andrea De Souza, Director