1. Distributed Drug Discovery William L. Scott Department of Chemistry and Chemical Biology Indiana University Purdue University Indianapolis, Indianapolis IN 46202 1

2. - The Goal: Interdisciplinary education of undergraduates. Accelerated discovery of drug leads for developing world or orphan diseases. - The Resources: Distributed and Integrated Simple, inexpensive, widely applicable research tools. Multiple (e.g.distributed) undergraduate labs. Spare/idle critical resources in industry and academia. IUPUIs Distributed Drug Discovery Project 2

3. Centralized vs. Distributed Problem Solving 3

4. Diagram Of A Distributed Problem Solving Process Applied To Drug Lead Discovery 4

5. Stage 1: Distributed Problem Solving Applied To Drug Discovery Computational Analysis Millions of candidatesHundreds of candidates 5

6. Some Current Examples of Distributed Computational Analysis in Drug Discovery Novartis: Currently has linked 2,700 company PCs in drug discovery. Goal is to link 70,000 company computers. http://folding.Stanford.edu/ (Folding@Home) www.Grid.org (Powered by United Devices software) Software: LigandFit (from Accelrys) Library sources: Asinex, Oxford, Maybridge, etc. Disease targets: Smallpox (examining 35 million drug candidates) Anthrax (examining 3.5 billion drug candidates) Cancer (See W.G. Richards, Virtual Screening Using GRID Computing: The Screensaver Project Nature Reviews Drug Discovery, 1, 551-555 (2002); also his web site at http://bellatrix.pcl.ox.ac.uk/index.html) 6

7. Stages 2 & 3: Distributed Synthesis and Screening 7

8. Key Question: Can Distributed Chemical Synthesis and Biological Screening be Carried Out in Undergraduate Laboratories? 8

9. Simple, well documented chemistry to relevant drug targets. - Use solid-phase combinatorial chemistry to substituted unnatural amino acids and peptidomimetics. Simple, inexpensive equipment to make the molecules. - Use a Bill-Board to conduct up 6 solid phase reactions at the same time. Academic laboratories will train students in solid-phase and combinatorial synthesis while simultaneously making new molecules as potential drugs. Requirements at the Chemistry Level 9

10. Some Peptidomimetic Virtual Libraries Available from Our Key Intermediate: Resin-Bound Unnatural Amino Acid 2 10

11. 11 Schematic of Potential Libraries Available

12. 12 Example of Library Levels

13. Ultimate GoalFirst Demonstration 13 Converting Theory to Practice With Undergrads

14. Inexpensive Components of Bill-Board Kit (For Up to 6 simultaneous Solid Phase Syntheses) 6, 3.5ml fritted glass reaction vessels Bill-Board, washing/drain tray, collection rack Commercial benzophenone imine of gly-Wang resin Bill-Board rotisserie for up to 48 simultaneous reactions 14

15. Fall 2004: Final Pilot Lab (Done) - Undergraduate chemistry lab (1 Section, 17 Students) incorporated past years refinements and evaluated, in duplicate, 8 new alkylating agents. Spring 2005: Full IUPUI Implementation (Done) - up to 20 new alkylating agents will be evaluated, in quadruplicate, by 80 students in 4 lab sections. Spring/Fall 2005: Other Institutions in Distributed Discovery - Replicate pilot lab in two or more institutions outside US: University of Barcelona, Moscow State University, Lublin School of Pharmacy (Poland) (Done) Fall/Spring 2005-2006: Involve Other Schools in Indianapolis - Train student from University of Indianapolis (Done), relay experience to undergrad lab at the University of Indianapolis in Spring or Summer of 2006 (in Process). Distributed Chemistry Discovery Time Table 15

16. Pressing IT Needs Enumeration of libraries based on chemistry and reagent availability. Recording and management of rehearsal results. Tracking of reagents, compounds made, and all associated data (e.g. analytical and biological). Making all these resources easily available to global distributed drug discovery community. 16

17. Distributed Drug Discovery Depends on simple technology, inexpensive equipment and underutilized resources (brains included!) to facilitate drug lead discovery for developing world diseases. Builds on interdisciplinary expertise. Provides students with opportunity to see how their work fits into a bigger picture and indicates how they can make a difference. Is rooted in the core scientific value of universal reproducibility. Requires commitment to free and widespread exchange of scientific ideas and information across geography and culture. 17