Science for Life

Drug Discovery Resources at Purdue

Andrew Mesecar, PhDDeputy Director, Purdue Center for Cancer ResearchWalther Professor of Cancer Structural BiologyDepartment of Biological Sciences and Department of Chemistry

iCTSI - Molecular Therapeutics & Drug Discovery – April 21st, 2014

• Biomol. Screening**• Comp. Chemistry• Medicinal Chemistry• NMR• Mass Spectrometry

• DNA Sequencing• Proteomics*• Metabolite Profiling*• Transgenic Mouse* • BioInformatics

• Comp. Chemistry **• Medicinal Chemistry**• Crystal & X-ray• NMR• Mass Spectrometry• Biophysical Analysis*• Structural Biology

• Biological Eval.• Transgenic Mouse*• Imaging*• Flow Cytometry*• Trans. Pharmacol.*

• Biological Eval.• Flow Cytometry*• Imaging*

Blue = CCSG Supported Shared ResourceBlack = Bindley Biosciences Center Supported Shared Resource* = Indiana CTSI Designated Core **In process

Center for Cancer Research and Bindley Biosciences CenterIntegrating Shared Resources into Drug Discovery at Purdue

Biomolecular Screening and Drug Discovery Core FacilityBindley Biosciences Center

We can currently screen up to 15K to 25K compounds per 8 Hour Day!

• 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 GeXPLarisa Avramovalva@purdue.edu

Shilpa Parakh

sparakh@purdue.edu

Drug Discovery and Development at Purdue

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)

Format96-well and 384-well at 10 mM in DMSODelivery with Pin Tools 200 nL or 6 nL

Purdue Compound Libraries (~220K)

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.

DrugDiscovery.Purdue.edu

Dr. Sergey Savinov

College of Science-IT and Purdue ITaP Provide Database and Server Maintenance

Computational and Medicinal Chemistry Shared Resource

Computational and Medicinal Chemistry Shared Resource

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

Basic Services Included with HTS in Biomolecular Screening Facility in Bindley

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

Antonella Pepe, PhD

Post-Doctorate Research with Professor Gunda GeorgDepartment of Medicinal Chemistry, Univ. Minnesota

Graduate Work with Prof. Iwao OjimaChemistry Department, SUNY Stony Brook

Formally at Frederick National Laboratory for Cancer Research - National Institutes of Health

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.

Computational and Medicinal Chemistry Shared Resource

Drug Discovery and Development at Purdue

High-Throughput Crystallization, Crystal Imaging and Crystal Optimization

Lead Optimization – Macromolecular Crystallography Shared ResourceDr. Nic Steussy (PCCR) & Dr. Dinesh Yernool (Bindley Biosciences)

LS-CAT

High-Throughput X-ray Data Collection

LRL-CAT

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Accelerating New Collaborations and Navigating Through Shared Resources for Drug Discovery

ScientistsDr. Larisa AvramovaShilpa ParakhDr. Sergey Savinov

ScientistsDr. Sergey SavinovDr. Antonella PepeDinesh Yernool

ScientistsDr. Ben Elzey-2D Cell CultureDr. Sophie Lelievre – 3D Cell Culture

ScientistsDr. Ben Elzey - MDEDr. Aaron Taylor-ImagingDr. Greg Knipp – PKDr. Steve Byrn - Formuation

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