Rapid and Efficient Fragment Screening of Influenza and Ebola Viral Targets to Enable Novel Drug Discovery
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This webinar preview will begin to discuss the use of ligand-observe NMR techniques for fragment screening of Influenza and Ebola viral targets for drug discovery.
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Rapid and Efficient Fragment Screening of Influenza and Ebola Viral Targets to Enable Novel Drug Discovery
- 1. Rapid and Efficient Fragment Screening of Influenza and Ebola Viral Targets to Enable Novel Drug Discovery Douglas R. Davies Senior Manager of Structural Biology Beryllium Discovery Corp. Copyright © 2017 Honeycomb Worldwide Inc.
- 2. page 2 Webinar Overview • Background on Beryllium – Seattle Structural Genomics Center for Infectious Disease collaboration – Fragment screening • Fragments of Life library • Screening methodologies • Case Studies – Influenza A – Filoviridae Targets (Ebola, Marburg) www.be4.com, info@be4.com, 24 January 2017
- 3. page 3 About Beryllium • Founded in 1998 as Emerald Biostructures – deCODE biostructures 2000-2008; Emerald Bio 2009-2014 – Name change to Beryllium 2014 • Contract research focused on structural biology – Bainbridge Island, WA (X-ray crystallography, 500 MHz NMR) – Bedford, MA (protein expression/purification, 700 MHz NMR) 700 MHz NMR in BedfordX-ray generator in Bainbridge Is. www.be4.com, info@be4.com, 24 January 2017
- 4. page 4 Fragment Screening Concept <confidential> | 25 January 2017 N N Drug-like HtS hit mw 350-450 IC50 ~1 mM N N Albert, JS; Fragment-based Lead Discovery in “Modern Approaches to Lead Discovery” Wiley Publications, 2010, 105 Optimized candidate IC50 0.01 mM Fragment hit mw 150-250 IC50 ~1000 mM N N N N Optimized candidate IC50 0.01 mM Use of small fragments allows reasonable sampling of chemical space with ~103 molecules
- 5. page 5 Saturation Transfer Difference (STD) NMR <confidential> | 25 January 2017 Off Resonance Io (Ligand Reference Spectrum) On resonance Isat (Saturated Spectrum) Difference Spectrum Selective Saturation Io - Isat = • “Ligand-observe” screening • No upper limit on protein target size • No isotopic labeling required • Short data acquisition time • False positive rate high—orthogonal methods (X-ray) for confirmation
- 6. page 6 • Viral polymerases are proven drug targets (HIV-RT, HCV) • Influenza virus RNA-dependent RNA polymerase is a heterotrimeric protein complex – Polymerase acidic (PA) protein – 2 Polymerase basic proteins (PB1 and PB2) • SSGCID structures of isolated PA-C-terminal domain showed conformational flexibility at PB1 peptide binding domain— possible target for SBDD Influenza Viral Polymerase www.be4.com, info@be4.com, 24 January 2017
- 7. page 7 Fragment Hits vs. Influenza A PA-CTD • Expected many of the hits to bind to the PB1 binding site (which is a hot spot for in silico binding and conformational change) • Series of chlorophenyl compounds bind to a surface site distal from the PB1 binding site. – Site is located in close proximity to the viral RNA (vRNA) loading site and a species specific differential loop. PB1 binding pocket Fragment binding site www.be4.com, info@be4.com, 24 January 2017
- 8. Copyright © 2016 Honeycomb Worldwide Inc. Click here to watch the complete webinar: or Click here for more information on this presentation: http://xtalks.com/Fragment-Screening-of- Influenza-Ebola-Viral-Target.ashx POWERED BY HONEYCOMB Copyright © 2017 Honeycomb Worldwide Inc.