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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 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 Drug Discovery at GRI GRI Capabilities Software Bioinformatics Genomics Biological Projects Cell & Animal Models Proteomics Target Identification & Validation Phase from academia, government, biotech and pharma Diagnostics Validated Target Assays Medicinal Chemistry Lead Compounds Cell & Animal Models HTS Computer Modeling Cell & Animal Systems Protein Production Protein Structure High Throughput Screening, Medicinal Chemistry, Computation and Protein Phase Drug Candidates Toxicological Testing Phase 1 Clinicals Drug Development } Drug Candidates Licensing, Co-Development, Pharma Partner Phase Pharma-Quality 250,000 Compound Library 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 High-Throughput Screening Plate::explorer + Opera imaging system ultraHTS system Evotec-Technologies/Perkin-Elmer Up to 100,000 samples/24 hours High-Throughput Screening Applications Opera Imaging Reader 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 >50,000 multi-color data points/24 hours 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 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.) GRI Compound Library 26 databases >4 million structures • 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 Vendor Database Remove duplicates MW filter Solubility 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 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 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. Protein Docking Studies Small Molecule Modeling 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 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 Further Information: Charles C. McOsker, PhD Director, Business Development & External Relations Genome Research Institute (513) 558-2569 (513) 885-2285 (cell) [email protected]