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Genome Research Institute University of Cincinnati. 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. GRI Capabilities. Research Programs

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Genome research institute university of cincinnati

Genome Research Institute

University of Cincinnati


Genome research institute university of cincinnati

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


Genome research institute university of cincinnati

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


Genome research institute university of cincinnati

Drug Discovery at GRI

GRI Capabilities

Software

Cell &

Bioinformatics

Animal

Models

Cell & Animal

Genomics

Proteomics

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

Production

Structure

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


Genome research institute university of cincinnati

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


Genome research institute university of cincinnati

High-Throughput Screening

Plate::explorer + Opera imaging system ultraHTS system

Evotec-Technologies/Perkin-Elmer

Up to 100,000 samples/24 hours


Genome research institute university of cincinnati

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

>50,000 multi-color data

points/24 hours


Genome research institute university of cincinnati

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 P&G’s Mason Business Center (~3500 sq. ft.)


Genome research institute university of cincinnati

26 databases

>4 million structures

VendorDatabase

Remove duplicates

MW filterSolubility Filter

Remove reactives,

Unusual groups,

& toxicophores

(80 substructures)

  • Lipinski Rule of Five

  • > 5 H-bond donors

  • MW < 500

  • c log P< 5

  •  N's + O's < 10

“Cleaned”database

GRI Compound Library

  • It’s NOT just a numbers game –

  • compound selection can greatly

  • enhance screening efficiency

  • Originally from P&G 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


Compounds selected for repository

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.


Molecular modeling virtual screening

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.


Genome research institute university of cincinnati

Protein Docking Studies

Small Molecule Modeling


Medicinal chemistry

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)


Genome research institute university of cincinnati

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


Genome research institute university of cincinnati

Further Information:

Charles C. McOsker, PhD

Director, Business Development & External Relations

Genome Research Institute

(513) 558-2569

(513) 885-2285 (cell)

[email protected]


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