Inquiry Immersion 2021 - DRUG DESIGN: Why is it so hard to design new small molecule drugs?

INSTRUCTORS

• James Fraser (Lead Instructor)
• Tom Goddard (Chimera tutorial)
• John Irwin (Docking lecture)
• Tanja Kortemme (Protein Design lecture)

FACILITY MANAGERS

• Liam McKay MSG Crystallography Facility - tour
• David Bulkley CryoEM Core Facility - tour

LOCATION The Zoom where it happens!

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

MINI COURSE DEI Focus

• Diversity: highlighting historically marginalized scientists
• Equity: how can access to resources be made more equitable
• Inclusion: tools that focus on outreach and public education

Schedule

Monday Jan 4 - 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 5 - 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.

Wednesday Jan 6 - 2:30-4PM

• CANCELLED

Thursday Jan 7 - 2:30-4PM

• Install ChimeraX before class
• Tom Goddard: ChimeraX demo
  • Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists.
  • VR links:
    • Opiod
    • Coronavirus

Friday Jan 8 - 2:30-4PM

• Tanja Kortemme: Rosetta and Biologics
  • De novo design of potent and selective mimics of IL-2 and IL-15
  • Engineered ACE2 receptor traps potently neutralize SARS-CoV-2
  • De novo design of picomolar SARS-CoV-2 miniprotein inhibitors.

Tuesday Jan 12 - 2:30-4PM

• David Bulkley: CryoEM facility tour
• Liam McKay: Tour of Crystallography facility
• Equity in topic choice, instrument access, financial incentives.
• Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking
• Watch this video ahead of time - and we will have a discussion

Thursday Jan 14 - 11AM-12PM

• final presentation!