Chembridge/ ChemDiv (VICB Collection) Newest collection to be used for full screening or on a percompound basis. Compounds 100,000 were selected based on physical properties and diversity. 160,000 Drug-like, diverse set of small molecules. 2,000 A wide range of biologically active and structurally diverse compounds. 50% drug components, 30% natural products, 20% other bioactive components. NIH Clinical Collection I and II 730 Small molecules that have history of use in human clinical trials. Cayman Lipid Library 1,000 Broad variety of bioactive lipids. Fesik Fragment Library Marnett Collection Roche Published Protein Kinase Inhibitor Library* Ion Channel Epigenetics Collection Enzo Kinase Inhibitor Library GSK Published Kinase Inhibitor Library** Diverse collection of fragment molecules from 8 vendors, rule 16,000 of 3 compliant, and filtered against non-specific and interfering molecules. 215 NSAID derivatives that contain cyclooxygenase inhibitors, PPAR-gamma activators and apoptosis inducers. Small molecule protein kinase inhibitors disclosed in peerreviewed scientific publications. 235 6,243 A collection from Life Chemicals targeted to ion channels compiled using 2D fingerprint similarity methodology. 51 A group of small molecule modulators with biological activity for use in epigenetic research. 80 The Screen-Well™ Kinase Inhibitor Library contains 80 known kinase inhibitors of well-defined activity. 349 A set of 349 small molecule kinase inhibitors spanning over 30 chemotypes that have been previously published by GlaxoSmithKline in peerreviewed scientific journals. Liquid Handling Other Instrumentation • Zinsser Calli Robot (10uL-4 mL, 8 independent probes) • Agilent Bravo (10 uL-250uL disposable tips) • Agilent Vprep (10 uL-250 uL disposable tips) • Labcyte Echo 555 & 555 OMICS Non-contact acoustic dispensers (2.5 nL-1 uL) • Thermo Combi Liquid Dispensers (uL amounts) • • • • • • • Services Brooks Universal Store + Cherry Pick Module Brooks X-cap Tube Decapper Fluid-X XDC-96-Pro Tube Decapper Agilent PlateLoc sealer Brooks X-Peel Plate seal remover BioMicroLab Volume Check Thermo CRS robotics compound management systems • Barcode Reading/Printing • Agilent Vspin Automated Centrifuge • Plate Shakers • Registration and sample tracking including: • New Chemical Entities (NCEs) synthesized at Vanderbilt • NCEs synthesized by external pharmaceutical industry collaborators • Externally purchased compounds • Stock sample preparation of NCEs • Compound Library Storage and Maintenance • Compound Distribution • Compound Reorders Compound Management Supported Labware for Storage and Distribution Matrix 96-well 2D Barcoded PP Tubes Septum or Screw Cap Labcyte PP 384-well plates Labcyte LDV 384-well plates Standard 96-well plates 96-well Deep Well Block Plates 1D and 2D barcoded glass vials Greiner 384-well round bottom plates Custom formats may also be considered Library plate stamping for primary screening assays* Well level/tube level cherry picking for secondary screening/hit confirmation Reorder powder compounds from vendor for additional confirmation and follow-up experiments Compound Requests and Distributions • Custom built Pipeline Pilot based “LIMS” system including user interface to request compounds, drive liquid handling equipment, create new samples in database and update sample quantity and storage information in real time Error Handling Systems and Communications • Pre-registration user error notifications • In-registration molecule duplicate checking • Post-registration Sharepoint based Issue Tracker ticket submission system Lead Optimization Support High-Throughput Screening Support Compounds registered and dissolved to 10mM and plated for further experiments (Additional dry powder can also be distributed) • Custom built Oracle database • Chemcart User Interface to chemical database • Custom built Chemcart + Pipeline Pilot based registration system Lead Optimization Compound Management Support Chemist submits compound+sample(s) information to Chemcart Registration Staging Area (Monday PM submission deadline) (Described in diagram to right) Newly created sample information is uploaded into Chemcart database via integrated Pipeline Pilot tools. Source tube is checked with Volume Check then stored in Universal Store at -20C. Properties updated in database (immediate) *Most HTS libraries are stored as 10 mM stock solutions in DMSO. Single compounds or small custom compound sets can also be cherry picked and distributed in small volumes. Compound Management registers compounds and samples into Chemcart Database via Pipeline Pilot (Tuesday) Fragment Based Screening Support 12-compound mixture plates produced for fragment based NMR screening* Deconvolution of mixtures into 3compound mixtures and/or single compound plated per well Titration plates produced for hit compounds Distribution of powder/liquid stock for X-ray crystallization experiments Compound Management cherry picks in Universal Store and dispenses compounds via liquid handler and users are notified that plates are ready for pickup (24 hr turnaround) Lead Optimization Compound Management Support (Described in diagram to right) *Fragment Library is stored as 200 mM stock solutions in d6-DMSO. Compound Management processes solid samples into 10 mM stock solutions in DMSO and transfers solution to 2D Matrix Tubes via Zinsser Liquid Handler. Samples stored at -20C in Universal Store (24 hr turnaround) Molecular Pharmacologists request weekly Primary Screening plates via Waveguide (PP) Compound Request System (may request at will) Molecular Pharmacologists, DMPK (in vitro and in vivo) request compounds via Waveguide (PP) Compound Request System for followup in a variety of tube/plate formats (may request at will) Compound Management dispenses compounds via liquid handler and users are notified that the requested samples are ready for pickup (24-48 hr turnaround) Newly created sample information is uploaded into Chemcart database via integrated Pipeline Pilot tools. Source tube is checked with Volume Check then stored in Universal Store at -20C. Properties updated in database (immediate) * In collaboration with Roche Pharmaceuticals ** In collaboration with GSK Pharmaceuticals Challenges Compound Libraries Spectrum Collection Description Compound Registration and Sample Tracking Informatics Tools and Services Vanderbilt Discovery Collection Size Instrumentation and Services Library Compound Management Process Our Mission Within the High Throughput Screening Core, Vanderbilt houses a cutting edge academic Compound Management facility which provides this critical function to both internal and external partners for a variety of drug discovery efforts at various stages of development. In addition to effectively managing Vanderbilt’s HTS plate/tube based libraries, a standard in many HTS facilities for the assistance of early stage hit identification, we also provide a variety of Compound Management services to numerous Hit-to-Lead and Lead Optimization efforts ongoing in the Vanderbilt Community. Vanderbilt Compound Management Future Directions • • • • • Mass Spec hit confirmation/QC Automated drop visualization (post-acoustic dispensing) Automated plate retrieval from Universal Store Automated plate sonication for mixing Non-standard database registration and sample tracking of compounds with undisclosed chemical structures (e.g. external collaborations) • Natural Products • siRNA Kristen Nailor Chemical Management Specialist Sherrell Reaves Research Assistant I