Relating Small Molecule Structure to Small Molecule Performance

1. Relating Small Molecule Structure to Small Molecule Performance Establishing structure-activity relationship (SAR) for novel disaccharides exposed to preadipocyte cell states Isaac Joseph

2. Why is finding SAR useful? • Drug development • Effect enhancement through structure optimization

3. How did we previously assess SAR? Visual inspection of data and structures • Introduces bias • Time -consuming Computational analysis – often used with isolated proteins • Doesn’t account for cellular context • Usually dealswith only onebiological outcome

4. How do I assess SAR? • Describe structure and performance • Alter structure description to match performance • Interpret results

5. structural descriptors regiochemistry How do we describe elements of small molecule structure?

6. structural descriptors stereochemistry How do we describe elements of small molecule structure?

7. structural descriptors appendages How do we describe elements of small molecule structure?

8. structural descriptors structure matrix How do we represent small molecule structure computationally? 64 small molecules 50 descriptors presence absence

9. What biological effects were measured? • 5 preadipocyte cell states • Wild-type brown preadipocyte • IRS 1 -/- brown preadipocyte • IRS 2-/- brown preadipocyte • 3T3- L1 white preadipocyte • Tunicamycin modified white preadipocyte • 2 measured effects • Lipid accumulation • Mitochondrial membrane potential

10. How do we represent biological effects computationally? performance matrix 64 small molecules 80 assays (2 columns each for +, - effects) effect no effect

11. How do I assess SAR? • Describe structure and performance • Alter structure description to match performance • Interpret results

12. Step 1: Calculate similarities between small molecules in performance performance matrix pairwise performance similarity 64 small molecules 80 assays effect no effect 64 small molecules 64 small molecules dissimilar similar

13. Step 2: Calculate similarities between small molecules in structure using partial description candidate structure matrix pick a subset structure matrix 64 small molecules pairwise structure similarity 64 small molecules 8 descriptors 64 small molecules 50 descriptors 64 small molecules presence absence dissimilar similar

14. Step 3: Check similarity between performance and structure pairwise performance similarity VS. pairwise structure similarity 64 small molecules 64 small molecules 64 small molecules 64 small molecules dissimilar similar dissimilar similar

15. Step 4: Change structural description until similarity between performance and structure is maximum pairwise performance similarity 64 small molecules 64 small molecules 64 small molecules 64 small molecules all descriptors selected descriptors optimized pairwise structure similarity pairwise structure similarity 64 small molecules 64 small molecules 64 small molecules

16. How do I assess SAR? • Describe structure and performance • Alter structure description to match performance • Interpret results

17. How do we know it’s working? performance matrix structure-performance similarity (correlation coefficient) columns permuted 22 times p < 0.046

18. selected descriptors What do the selected structures mean? optimized structure similarity matrix performance similarity matrix 8 small molecules

19. Acknowledgements Analysis Paul A. Clemons (mentor) Joshua C. Gilbert Nicole E. Bodycombe Chemistry Micha Fridman Tetsuya Tanikawa Daniel Kahne Biology Bridget K. Wagner Administration Shawna L. Young Bruce Birren