Inquiry Immersion 2019-20 - DRUG DESIGN: Why is it so hard to design new small molecule drugs?

INSTRUCTORS

• James Fraser (Lead Instructor)
• Tom Goddard (Chimera tutorial January 8)
• John Irwin (Docking lecture Jan 9)
• Tanja Kortemme (Protein Design leture January 14)

FACILITY MANAGERS

• Liam McKay MSG Crystallography Facility - tour and practical session Jan 7
• David Bulkley CryoEM Core Facility - tour Jan 15

LOCATION Genentech Hall 227 - teaching lab (beside Cafe 24)

OVERVIEW

Structure-based drug design promises to revolutionize drug discovery, yet despite decades of promise, progress remains intermittent. This course will give students an appreciation for the experimental and computational advances that have led to this optimism, while also pointing out the limitations that currently prevent completely unattended design.

MINI COURSE OBJECTIVES

• Identify an urgent and significant gap in medical knowledge and/or practice.
• Propose rationale and novel strategies to address that gap in medical knowledge and/or practice using tools and techniques germane to the relevant Domain(s) of Science.
• Engage with researchers working on the topic explored and collaborate on potential scholarly research.

TOPIC OBJECTIVES

• Employ visualization software to examine small molecule drugs in their binding sites.
• Contrast different discovery strategies (fragments, virtual screening, biologics)
• Propose modification to molecules to increase their potency

Schedule

Monday Jan 6 - 2:30-4PM

• James Fraser: Intro to class and contrasting kinase and phosphatase drug discovery
  • Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase
  • Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.
• install ChimeraX

Tuesday Jan 7 - 2:30-4PM

• James Fraser: Fragment-based design and Crystallography 101
  • Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.
  • Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR
  • An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering
• Liam McKay: Tour of Crystallography facility
  • Crystalizing Lysozyme

Wednesday Jan 8 - 2:30-4PM

• Tom Goddard: ChimeraX demo
  • Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists.
  • VR experience in Genentech Hall N453

Thursday Jan 9 - 2:30-4PM

• John Irwin: Docking what works and what doesn’t
  • What docking is, how it works, and why it is hard; a review of some notable success stories “what docking can do for you” and failures; a detailed look at 2 or 3 stories, focusing on how to run a docking campaign, and what to expect from the outcome, with results.
  • resources DOCK Blaster, ZINC, DUDE, and how to use them.

Tuesday Jan 14 - 2:30-4PM

• Tanja Kortemme: Rosetta and Biologics
  • De novo design of potent and selective mimics of IL-2 and IL-15
  • Proof of principle for epitope-focused vaccine design
  • Computational design of a modular protein sense-response system

Wednesday Jan 15 - 2:30-4PM

• David Bulkley: CryoEM facility tour
• James Fraser: Discussion of new themes in drug discovery - DELs, PROTAC, covalent inhibition, cryoEM