3decision®: Bringing structural data analytics to the masses
- 1. Bringing structural data analytics to the masses Peter Schmidtke, PhD
- 2. Agenda Background of Structure based drug design ▪ Why ▪ How ▪ What’s wrong with that? 3decision ▪ How we address main caveats in SBDD ▪ Some capabilities ▪ Perspectives
- 4. 01 Background How many projects benefit from structures? ▪ Small Companies > 25% – 100% (very dependent on the company) ▪ Top20 Pharma > ~50% on average Target Identification 20M$* Investigational Drug Filing 50% *Stevens, R.C. Drug Discov. World 4:35,Summer 2003.
- 5. 01 Background What do you use structures for?* ▪86% Hit identification ▪ 100% Lead Optimization ▪ 72% Homology Modeling ▪14% Target Validation, Off target prediction, DMPK 100M€ / company for structure production (last decade) 100% 86% Stevens, R.C. The cost and value of three-dimensional protein structure. Drug Discov. World 4:35, Summer 2003. *Schmidtke P, survey results 2016
- 6. Structures 60000 40000 20000 0 80000 100000 120000 140000 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 PDB: Cumulated number of structures released each year Total x SAXS, XFEL, CryoEM … x docking + homology models + conformations from molecular dynamics
- 7. 01 Background What do you need to do structure based drug design? ▪ Structures ▪ People that make sense out of structures > Modelers > Medicinal chemists > Structural biologists
- 8. How we work The way we work most of the time:
- 9. How we work Most of the time
- 10. How we work Most of the time
- 11. How we work Most of the time
- 12. How we work Most of the time ▪ Save project work on a shared drive ▪ Project eventually stops
- 13. How we work Most of the time ▪ Save project work on a shared drive ▪ Project eventually stops Current main issues ▪ Work is not reusable / reproducible ▪ Lots of effort for gathering and shaping data ▪ You need strong expertise ▪ Amount of structures is large (will grow faster)
- 14. General Observation Structural data & knowledge is heavily underutilized 14
- 16. Addressing main issues Main issues ▪ Amount of structures is large (will grow faster) ▪ Lots of effort for gathering and shaping data ▪ Work is not reusable ▪ You need strong expertise
- 17. Large amount of structures? Contains full PDB today ▪ > 130k structures ▪ Registers conformations (NMR) ▪ > 250k conformations ▪ Automated structure data curation Data model is ready today for future increase
- 18. Lots of effort for gathering and shaping data?
- 19. Work is not reusable? Molecular Modeler
- 20. You need strong expertise? A lot of standard work can be streamlined ▪ What ligand binds where? ▪ How to improve selectivity profile of my chemical series? ▪ Does this molecule fit here? ▪ What putative off targets I should monitor? ▪ What binds to my pocket? ▪ … A lot of complicated work can be made more accessible
- 21. 3DECISION A tiny fraction of its capabilities 03
- 22. First simple use case What binds to my pocket?
- 24. Open 1 structure
- 28. Share this with my colleagues
- 29. What binds to my pocket? 3decision ▪ Results in seconds ▪ 100% reproducible ▪ 100% complete ▪ Up to date Same done by a human ▪ Results in hours ▪ Not reproducible ▪ Probably not complete ▪ Snapshot at a certain time Gain in productivity > 100 fold
- 30. A more complex use case What putative off-targets should I monitor?
- 34. What putative off targets I should monitor? 3decision ▪ Results in seconds-minutes ▪ 100% reproducible ▪ Up to date Same done by a human ▪ Results in days ▪ Not reproducible ▪ Does not include most recent findings
- 35. PERSPECTIVES 04
- 36. PERSPECTIVES Advanced collaboration functionalities Local structure comparison (we’re the only ones doing it so far) Generic molecular interaction comparison (ongoing PhD project) Signup for our early adopters program : ▪ 3decision.discngine.com
- 37. Interested to know more? Peter Schmidtke peter@discngine.com @pschmidtke Thomas Blarre thomas@discngine.com @thomasBlarreDNG #3decision 3decision.discngine.com
- 39. Presented at the Global Pharma R&D Informatics Congress. To find out more, visit: www.global-engage.com