Genome Research Institute

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Genome Research Institute University of
Cincinnati
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Genome Research Institute

• Housed in facility donated by Aventis
  Pharmaceuticals
• 360,000 sq. ft. of office, laboratory and
  vivarium space
• Currently houses 38 PIs, 350 total researchers

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GRI Capabilities

• Research Programs
• Molecular Mechanisms of Disease
• studies on the importance of aberrant
  pathway signaling in cancer and
• in metabolic diseases such as obesity
  and diabetes
• Obesity and Diabetes
• studies on the regulation of energy
  balance and glucose homeostasis
• in obesity and Type 2 diabetes
• studies on regulation of responses to
  environmental stressors with
• emphasis on behavioral and dietary
  interventions to optimize
• performance
• Lipid Metabolism
• elucidation of the roles of brain,
  intestine, and liver in regulation of
• plasma lipid metabolism, and the
  consequential effects on inflammation,
• cancer, atherosclerosis, obesity and
  development

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Drug Discovery at GRI
GRI Capabilities
Software
Cell
Bioinformatics
Animal
Models
Cell Animal
Proteomics
Genomics
Diagnostics
Models
Biological Projects from academia, government,
biotech and pharma
Pharma-Quality250,000 Compound Library
Validated
Target Identification Validation Phase
Target
Assays
Medicinal
HTS
Chemistry
Computer
Lead
Modeling
Compounds
Cell Animal
Systems
Protein
Protein
Structure
Production
High Throughput Screening, Medicinal Chemistry,
Computation and Protein Phase

Toxicological Testing
Drug
Drug
Phase 1 Clinicals
Candidates
Candidates
Drug Development
Licensing, Co-Development, Pharma Partner Phase
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Drug Discovery at GRI

• Core Facilities
• Proteomics
• drug target identification
  characterization
• drug candidate mechanism of action
• method development for
  posttranslational modification determination
• Protein Production
• production and purification of
  recombinant proteins (E. coli)
• Model Organisms
• use of Drosophila, zebrafish, and
  mouse to identify and validate potential
• drug targets
• Behavioral Studies
• characterization of rodent behavior in
  models of anxiety, learning and
• memory, motor function and locomotion,
  and drug side effects
• Mouse Metabolic Phenotyping Center (NIDDK)
• identification and validation of drug
  targets through characterization of lipid
• metabolism, cardiovascular renal
  function, energy homeostasis, and
• behavior
• High-Throughput Screening
• rapid identification of structural
  leads for drug discovery programs

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High-Throughput Screening
Plateexplorer Opera imaging system ultraHTS
system Evotec-Technologies/Perkin-
Elmer
Up to 100,000 samples/24 hours
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High-Throughput Screening
Applications Whole cell fluorescence assays
Cell viability, cell differentiation, cell
proliferation, cytotoxicity, apoptosis,
transporter phenomena Cell signaling assays
Calcium flux, second messengers, ion channels,
membrane potential Gene expression assays
Expression of house-keeping and reporter
genes, gene activity and protein regulation,
RNAi Membrane receptor assays Ligand binding,
receptor activation and desensitization,
translocation and endocytosis, recruitment of
signaling molecules Translocation assays
Target molecule redistribution Morphological
assays Neurite outgrowth, cell
differentiation, cell adhesion and spreading
Opera Imaging Reader
gt50,000 multi-color data points/24 hours
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Compound Repository

• Haystack Neat Compound Storage
• Capacity 200,000 bottles
• Current 207,000 bottles
• Freezer storage when appropriate
• Solar (Solution Archive) DMSO solutions
• Capacity 1.8 million tubes, 10,000 deep well
• (96) plates, 13,600 shallow well (384)
  plates
• Current 338,000 compounds in 383,400
• tubes, 1862 deep wells and 2332 shallow
  wells
• Compound handling and dissolution instruments
• Housed at PGs Mason Business Center (3500 sq.
  ft.)

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GRI Compound Library

• Its NOT just a numbers game
• compound selection can greatly
• enhance screening efficiency
• Originally from PG Pharma and
• represents a 22M investment
• Selected based on drug-like
• properties and to maximize
• structural diversity within a
• 6-dimensional drug-like space
• Both external (commercial suppliers)
• and internal discovery and
• combinatorial chemistry programs
• used as sources
• 250,000 compounds
• Software to rapidly expand around
• structural leads identified

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Compounds Selected for Repository

• Defined by experienced medicinal chemists
• Broad, uniform distribution across Drug Space
  with concentrations of density in key areas from
  directed purchase and in house synthesis.
• Compare to 5 vendor screening collections
• 3,000 to 500,000 compounds
• 27 - 56 of vendors compound collections do NOT
  meet criteria for drug-like
• UC Compound collection is 2X to 100X more
  chemically diverse across Drug Space.
• Vendor Libraries are inherently predisposed to
  clustered groupings.
• We picked the best, most relevant compounds from
  each.

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Molecular Modeling Virtual Screening

• Protein Ligand Docking
• Rapid docking algorithms for high volume virtual
  screening of drug
• targets against all commercially available
  compounds
• Detailed dynamic follow-up docking for enhanced
  accuracy and prediction
• of binding interactions.
• Pharmacophore Modeling
• Abstracting key pharmacophoric elements from
  molecular series, and
• using this as the basis for virtual screening.
• Nearest-Neighbor Analysis (hit expansion)
• Shape matched and general similarity based
  methods to identify compounds similar to leads.

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Protein Docking Studies
Small Molecule Modeling
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Medicinal Chemistry

• Infrastructure
• 3300 sq. ft. of laboratory space available
• Synthesis Capability
• Flexibility built in to move between single
  compound and small library synthesis (for SAR
  determination)
• Compound Characterization
• Full Complement of Purification (Prep
  analytical HPLC) and Analytical tools (NMR, LCMS)

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Genome Research Institute
What can we provide?

• Research expertise in signaling pathways,
  cancer, and metabolic
• regulation
• An academic drug discovery center with
  experienced leaders drawn
• from the pharma industry
• State of the art high-throughput and
  high-content screening capability
• Access to a highly-diverse library of drug-like
  compounds for screening
• Molecular modeling and in silico screening
• Behavioral and mouse phenotyping core facilities

What are we looking for?

• Drug targets for screening
• Libraries of novel compounds
• Drug discovery collaborations
• Research collaborations in areas of interest
• Opportunities to create closer interactions with
  biotech and pharma
• companies

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Further Information
Charles C. McOsker, PhD Director, Business
Development External Relations Genome Research
Institute [phone] [phone]
(cell) charles.mcosker_at_uc.edu