Science for Life Drug Discovery Resources at Purdue Andrew Mesecar, PhD Deputy Director, Purdue Center for Cancer Research Walther Professor of Cancer Structural Biology Department of Biological Sciences and Department of Chemistry iCTSI - Molecular Therapeutics & Drug Discovery – April 21st, 2014 Center for Cancer Research and Bindley Biosciences Center Integrating Shared Resources into Drug Discovery at Purdue Target Discovery & Selection • • • • • DNA Sequencing Proteomics* Metabolite Profiling* Transgenic Mouse* BioInformatics Hit-2-Lead Discovery • • • • • Biomol. Screening** Comp. Chemistry Medicinal Chemistry NMR Mass Spectrometry Lead Optimization • • • • • • • In Vitro Studies Comp. Chemistry ** • Biological Eval. Medicinal Chemistry** • Flow Cytometry* Crystal & X-ray • Imaging* NMR Mass Spectrometry Biophysical Analysis* Structural Biology Blue = CCSG Supported Shared Resource Black = Bindley Biosciences Center Supported Shared Resource * = Indiana CTSI Designated Core **In process In Vivo & Preclinical Studies • • • • • Biological Eval. Transgenic Mouse* Imaging* Flow Cytometry* Trans. Pharmacol.* Biomolecular Screening and Drug Discovery Core Facility Bindley Biosciences Center We can currently screen up to 15K to 25K compounds per 8 Hour Day! Larisa Avramova [email protected] Shilpa Parakh [email protected] • 96-well, 384-well and 1536-well format • Biochemical and Cellular Assays • Automated liquid-handling Robotics – 3 Biomek FX Systems and others, QPix • VP Scientific 384-Well Pin Tools • Multi-Mode Plate Readers • High-throughput cloning and protein expression, purification • Chemical and biologic screening • HT PCR and kinetic PCR • Multiplex genetic analyzer – Beckman GeXP Purdue Compound Libraries (~220K) ChemBridge DiverSet (30,000) ChemBridge CNS Set (20,000) ChemBridge NovaCore (50,000) Asinex Lead/Drug Like (60,000) LifeChemicals Cherry Picked (30,000) ChemBridge-Cherry Picked (25,000) ASDI Lead/Drug Like (6,800) ChemDiv Fragment (2,000) LOPAC1280 Pharma Active (1,280) Collaboration compounds (>1,000) Natural product library (~1,500) Format 96-well and 384-well at 10 mM in DMSO Delivery with Pin Tools 200 nL or 6 nL Drug Discovery and Development at Purdue Filling in ‘Chemical Space’ Compound Library Design & Sharing with Notre Dame and IU Chemical Space Coverage of Purdue and IU Compound Libraries. 3D Principle-component analysis of Drug-Like Properties. Only the portions of the library closest in chemical space to the compounds in the LOPAC® library are shown. Computational and Medicinal Chemistry Shared Resource DrugDiscovery.Purdue.edu Dr. Sergey Savinov College of Science-IT and Purdue ITaP Provide Database and Server Maintenance Computational and Medicinal Chemistry Shared Resource Cheminformatics and Structure-Based Design component was Established in 2012 via funding from Center for Cancer Research, Walther Cancer Foundation (Mesecar Grant) Discovery Park and Indiana CTSI Basic Services Included with HTS in Biomolecular Screening Facility in Bindley Compound Database –Web-based Oracle database using Dotmatics suite of programs (Browser) Cheminformatics Analysis (Compound Cluster & Substructure Analysis) –Extensive Analysis Suite of Programs via Dotmatics software platform (Browser, Vortex, Gateway, Studies, Notebook, Nucleus, Pinpoint) or Canvas in the Schrödinger Small Molecular Suite of Programs Enhanced Services that can be used in Conjunction with HTS Protein Structural Analysis & Homology Modeling In silico screening – Against our in-house 220K compound library, Zinc database etc. Can provide enrichment factor for choosing libraries and individual plates to test. Schrödinger Small Molecular Suite of Programs Computational Docking – Flexible ligands and Flexible Receptor capabilities. Other - 2D/3D QSAR, Core Hopping, Predictive ADMET Computational and Medicinal Chemistry Shared Resource Medicinal Chemistry Core Component was Established October 21st, 2013 with support from the Walther Cancer Foundation. Support of HTS, hit-2-lead follow-up (SAR) and scale-up for animal studies. Long-term, this shared resource will expand to include non-cancer related projects to support Purdue and CTSI faculty as a campus and CTSI resource. Formally at Frederick National Laboratory for Cancer Research - National Institutes of Health Post-Doctorate Research with Professor Gunda Georg Department of Medicinal Chemistry, Univ. Minnesota Graduate Work with Prof. Iwao Ojima Chemistry Department, SUNY Stony Brook Antonella Pepe, PhD Lead Optimization – Macromolecular Crystallography Shared Resource Dr. Nic Steussy (PCCR) & Dr. Dinesh Yernool (Bindley Biosciences) High-Throughput Crystallization, Crystal Imaging and Crystal Optimization LS-CAT LRL-CAT High-Throughput X-ray Data Collection Drug Discovery and Development at Purdue Accelerating New Collaborations and Navigating Through Shared Resources for Drug Discovery Target Discovery & Selection iCTSI or Center Programs • CIS • CSB • MC • DDMS Hit-2-Lead Discovery Scientists Dr. Larisa Avramova Shilpa Parakh Dr. Sergey Savinov Lead Optimization In Vitro Studies Scientists Dr. Sergey Savinov Dr. Antonella Pepe Dinesh Yernool Scientists Dr. Ben Elzey-2D Cell Culture Dr. Sophie Lelievre – 3D Cell Culture In Vivo & Preclinical Studies Scientists Dr. Ben Elzey - MDE Dr. Aaron Taylor-Imaging Dr. Greg Knipp – PK Dr. Steve Byrn - Formuation 10
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