1. One Scientific Career(Computers in Biology) Philip E. Bourne PhD [email_address] http://www.sdsc.edu/pb http://www.sdsc.edu/~bourne

2. The Life of One Scientist The Early Years So That You Might Not Make the Same Mistakes

My high school teacher Mr. Wilson said I would be a failure at chemistry

My PhD is in chemistry

The opportunity to live in different places shaped my life

3. 40+ Years Later

Good friends are forever

4. BSc (Hon) It was About Then I Began to Understand Myself But I Still Made Mistakes 5. PhD The Molecular Basis of Cancer Treatment

I thought I was at the center of the scientific universe

I later discovered I was actually in deep space

6. I Love ComputersCirca 1974

Your head will tell you stuff

Your heart will tell you something different

Follow your heart

7. Postdoctoral Work The Molecular Basis of How the Body Works

Regrets: never learnt another language

8. Studying Iron Metabolism 9. Some Things Stay with You Your Whole Life 10. I Got Involved in Open Source Software

Look for the signs that will shape your later life

11. Senior Scientist Columbia University New York

Driven not by career but wanting to live in New York City

12. The IT Years

Thought more about money than science

Paid the price in later years only now catching up

Do I have regrets?- Nah

Stated another way science is for the long haul and it is about establishing a reputation

May have wasted the most productive years

2007 Ten Simple Rules for Doing Your Best Research, According to Hamming PLoS Comp. Biol., 3(10): e213 13. The Authoring Years 14.

Make the most of every day

15. Got Involved with the The Human Genome Was Only Possible by Applying Computers to Problems in Biology

Realized what was coming and leveraged the possibilities

Built on existing strengths

Was prepared to move

Picked the best place

16. Came to UCSD to Apply Computers to Big Biological Problems

Possibly the best place in the world to do computational biology

17. 18. The Growth of Data is A Major Driver in Biology Number of released entries Year 19. The PDB was a Big Plus

Money talks even in academia

Satisfied my needs that engineer again

High visibility

Used it to leverage my research

20. Today - Big Research Questions in the Lab

Can we improve how science is disseminated and comprehended?

What is the ancestry of the protein structure universe and what can we learn from it?

Are there alternative ways to represent proteins from which we can learn something new?

What really happens when we take a drug?

Can we contribute to the treatment of neglected {tropical} diseases?

August 14, 2009 21.

We know very little about how the major drugs we take work

We know even less about their side effects

Drug discovery seems not to have moved into theomicsera

The cost and time of bringing a drug to market is huge ~ $1 Bn

The cost of failure is even higher e.g., Vioxx~ $5 Bn

Fatal diseases are neglected because they do not make money

Motivation Skaggs School of Pharmacy 22. Why Dont We Have More and Better Drugs?

Tykerb Breast cancer

Gleevac Leukemia, GI cancers

Nexavar Kidney and liver cancer

Staurosporine natural product alkaloid uses many e.g., antifungal antihypertensive

Collins and Workman 2006Nature Chemical Biology2 689-700 23. Implications

Ehrlichs philosophy of magic bullets targeting individual chemoreceptors has not been realized

Stated another way The notion of one drug, one target, one disease is a little nave in a complex system

24. What Do These Off-targets Tell Us?

Potentially many things:

• Nothing

• How to optimize a NCE

• A possible explanation for a side-effect of a drug already on the market

• A possible repositioning of a drug to treat a completely different condition

• The reason a drug failed

• A multi-target strategy to attack a pathogen

25. Need to Start with a 3D Drug-Receptor Complex - The PDB Contains Many Examples Computational Methodology Generic Name Other Name Treatment PDBid Lipitor Atorvastatin High cholesterol 1HWK, 1HW8 Testosterone Testosterone Osteoporosis 1AFS, 1I9J .. Taxol Paclitaxel Cancer 1JFF, 2HXF, 2HXH Viagra Sildenafil citrate ED, pulmonary arterial hypertension 1TBF, 1UDT, 1XOS.. Digoxin Lanoxin Congestive heart failure 1IGJ 26. A Reverse Engineering Approach toDrug Discovery Across Gene Families Characterize ligand bindingsite of primary target(Geometric Potential) Identify off-targets by ligandbinding site similarity (Sequence order independentprofile-profile alignment) Extract known drugsor inhibitors of theprimary and/or off-targets Search for similar small molecules Dock molecules to bothprimary and off-targets Statistics analysisof docking scorecorrelations Xie and Bourne 2009Bioinformatics 25(12) 305-312 27. The Problem withTuberculosis

One third of global population infected

1.7 million deaths per year

95% of deaths in developing countries

Anti-TB drugs hardly changed in 40 years

MDR-TB and XDR-TB pose a threat to human health worldwide

Development of novel, effective, and inexpensive drugs is an urgent priority

28. Summary of the TB Story

Entacapone and tolcapone shown to have potential for repositioning

Direct mechanism of action avoidsM. tuberculosisresistance mechanisms

Possess excellent safety profiles with few side effects already on the market

In vivosupport

Assay of direct binding of entacapone and tolcapone to InhA reveals a possible lead with no chemical relationship to existing drugs

Kinnings et al. 2009PLoS Comp Biol5(7) e1000423 29. SMAP p-value < 1e-5 drugs TB proteins p < 1e-7 p < 1e-6 p < 1e-5 30. 31. Motivation 32. 33. There Have Been a Few Ah Hah Moments 34. Current Career Goals

Crowd source the twenty first century printing press

Make a significant contribution to peoples lives as a result of work on a neglected disease

Inspire young minds

35. A Few of Lifes Lessons

Manage by doing not by saying

Treat people well you will feel good and it pays off

Every day ask yourself if you are content if the answer is no do something else

36. Life Is About Balance 37. More Information

Podcast on off-targeting -http://www.scivee.tv/node/15685

Google PLoS Collections 10 Rules

Great Motorcycle Journeys of the World - http://www.travelblog.org/Bloggers/OFL/