George S. Cowan, Ph.D. Computer Aided Drug Discovery

1. Problems and Opportunitiesfor Machine Learning in Drug Discovery(Can you find lessons for Systems Biology?) George S. Cowan, Ph.D. Computer Aided Drug Discovery Pfizer Global Research and Development, Ann Arbor Labs CSSB, Rovereto, Italy 19 April 2004

2. Working as a Computer Scientist in a Life Sciences field requires an array of supporting scientists Thanks to: Cheminformatics Mentors and Colleagues:John Blankley Alain Calvet David Moreland Project Colleagues:David Wild Kjell Johnson Academic: Peter Willett Robert Pearlman Risk Takers:Eric Gifford Mark Snow Christine Humblet Mike Rafferty

3. Drug Discovery and Development Discern unmet medical need Discover mechanism of action of disease Identify target protein Screen known compounds against target Synthesize promising leads Find 1-2 potential drugs Toxicity, ADME Clinical Trials Biology Chemistry Pharmacology

5. Lock and Key Model

6. Virtual HTS Screening Virtual Screening Definition estimate some biological behavior of new compounds identify characteristics of compounds related to that biological behavior only use some computer representation of the compounds HTS Virtual Screening is Not QSAR/QSPR Based on large amounts of easy to measure observations Uses early stage data from multiple chemical series (no X-ray Crystallography) Observations are not refined (Percent Inhibition at a single concentration) Looking for research direction, not best activity

7. Promise of Data Mining Data Mining Works with large sets of data Efficient Processing Finds non-intuitive information Methods do not depend on the Domain (Marketing, Fraud detection, Chemistry, …) Alternative Data Mining Approaches Regression - Linear or Non-Linear - PLS Principal Components Association Rules Clustering Approach - Unsupervised - Concept Formation Classification Approach - Supervised

8. Overview (1) Virtual Screening Challenges to Machine Learning No single computer representation captures all the important information about a molecule The candidate features for representing molecules are highly correlated Features are entangled Multiple binding modes use different combinations of features Multiple chemical series / scaffolds use the same binding mode Evidence that some ligands take on multiple conformations when binding to a target Any 4 out of 5 important features may be sufficient

9. Overview (2) More Challenges to Machine Learning Training data and validation data are not representative Measurements of activity are inherently noisy Activity is a rare event; target populations are unbalanced Classification requires choosing cutoffs for activity There is no good measure for a successful prediction Many data mining methods characterize activity in ways that are meaningless to a chemist Data mining results must be reversible to assist a chemist in inventing new molecules that will be active (inverse QSAR)

10. Overview (3) Deep Challenges to Machine Learning No free lunch theorem Science is different from marketing

11. No Single Computer Representation captures all the important information • How do we characterize the electronic “face” that the molecule presents to the protein? • Grid of surface or surrounding points with field calculations • Conformational flexibility • 3-D relationships of pharmacophores • Complementary volumes and surfaces • Complementary charges • Complementary hydrogen bonding atoms • Similar Hydrophbicity/Hydrophilicity • Connectivity: Bonding between Atoms (2-D) • pharmacophore info is implicitly present to some extent • not biased toward any particular conformation • Presence of molecular fragments (fingerprints) • Other: Linear (SLN, SMILES)? Free-tree?

12. Pharmacophores

13. Representation of Chemical Structures (2D) Aspirin

14. - augmented atoms - atom pairs - atom sequences - ring compositions BCI Chemical Descriptors • Descriptors are binary and represent

15. We don’t have the right descriptors, but we have thousands that are easy to compute • Thousands of molecular fragments • Hundreds of calculated quasi-physical properties • Hundreds of structural connectivity indicators • Much of this information is redundant

16. Feature Interaction andMultiple Configurations for ActivityRequire Disjunctive Models • Multiple binding modes where different combinations of features contribute to the activity(including non-competitive ligands) • Multiple chemical series / scaffolds use the same binding mode • Any 3 out of 4 important features may be sufficient • Evidence that some targets require multiple conformations from a ligand in order to bind

17. Non-competitive Binding

18. Non-competitive Binding

19. Unbalanced target populations (activity is a rare event) • About 1% of drug-like molecules have interesting activity • Most of our experience in classification methods is with roughly balanced classes • Predictive methods are most accurate where they have the most data (interpolation), but where we need the most accuracy is with the extremely active compounds (extrapolation) • Warning: Your data may look balanced • True population of interest: • new and different compounds • Unrepresentative HTS training data: • What chemists made in the past • Unrepresentative follow-up compounds for validation: • What chemists intuition led them to submit to testing

20. Populations next

21. 2 1 0 Score HIV -1 -2 -3 0 1000 2000 3000 4000 5000 6000 Cipsline, Anti-infectives Our models are accurate on the compounds made by our labs

23. Kappa= 0.147

24. Choosing cutoffs for activity and cutoffs for compounds to pursue • Overlapping ranges of Inactive and Active • Cost of missing an active vs. cost of pursuing an inactive

25. Ideal vs. Actual HTS Observations

27. 140 140 120 120 100 100 80 80 60 60 40 40 20 20 0 0 1 10 100 1000 10000 0 1000 2000 3000 4000 5000 # tested Upper Ref # of active retrieved Random Virtual Screening# of active retrieved vs # of compounds tested # tested

28. 130 110 100 80 60 40 20 # of active 0 2 20 200 2000 20000 # of compounds screened We use the log-linear graph to compare methods at different follow-up levelsSee how 3 different methods perform at selecting 5, 50, or 500 compounds to test RP SOM LVQ Reference Random

29. Noise in measurement of activity • Suppose 1% active and 1% error, then our predicted actives are 50% false positives • This is out of the range of data-mining methods (but see “Identifying Mislabeled Training Data”, Brodley & Friedl, JAIR, 1999) • Luckily, the error in measuring inactives is dampened • Methods can take advantage of the accuracy in inactive information in order to characterize actives • On the other hand, inactives have nothing in common, except that they are the other 99%

30. Mysterious AccuracyORNeural Networks are great, but what are they telling me? We have a decision to make about data mining goals: • Do we try to:Outperform the chemist or engage the chemist We need to assist a chemist in inventing new molecules that will be active (inverse QSAR) We need to characterize activity in ways that are meaningful to a chemist

31. No Free Lunch Theorem • Proteins recognize molecules • Proteins compute a recognition function over the set of molecules • Proteins have a very general architecture • Proteins can recognize very complex or very simple characteristics of molecules • Proteins can compute any recognition function(?) • No single data-mining/machine-learning method can outperform all others on arbitrary functions • Therefore every new target protein requires its own modeling method • “Cheap Brunch Hypothesis”: Maybe proteins have a bias

32. Science, Not Marketing • We are looking for hypotheses that are worth the effort of experimental validation(not e-marketing opportunities) • Data-mining rules and models need to be in the form of a hypothesis comparable to the chemist’s hypotheses • Chemists need tools that help them design experiments to validate or invalidate these competing hypotheses • HTS is an experiment in need of a design

33. Conclusion • Machine-learning tools provide an opportunity for processing the new quantities of data that a chemist is seeing • The naïve data-mining expert has a lot to learn about chemical information • The naïve chemist has a lot to learn about data-mining for information

34. If there are so many problemswhy are we having so much fun? Maybe we’ve stumbled into the cheap brunch