Topics in Structure-Based Molecular Design in Drug Discovery

1. Lecture CourseETH Zurich, Spring Semester 2011 byKlaus Müller Topics in Structure-Based Molecular Design in Drug Discovery Problem Set for Examination use same ppt-file for your answers & submit by e-mail to klaus.mueller@roche.com deadline for submission: 11-May 2011 satisfactory answers will earn 1 Credit Point have fun!

2. Problem 1 (18 points) The 6 heterocyclic structures shown on the next 6 slides have been published in the literature 1-a: To each of these structures, assign the appropriate conformational class of type 7R-ene, 7R-diene, 7R-ene-ene, or 7R-triene. (6 points) 1-b: Are the 7-ring conformations found in the respective X-ray crystal structures according to your expectations? Give reasons. (6 points) 1-c: Comment on the arrangements of substituents on the 7-membered rings (6 points)

3. M. Ito etal., Angew.Chem. IE 48, 1324 (2009) DOSFUN

4. A.G.M. Barrett et al., J Org Chem 65, 3716 (2000) WIMWEU

5. M. Qadir etal., J Org Chem70, 1545 (2005) YANYAO

6. A.G.M. BL Yuan et al., Chin J Struct Chem 17, 459 (1998) HEWQEF

7. E.J. Trybulski et al., J Med Chem 26, 1596 (1983) CEDBAO

8. C. del Pozo et al., Eur J Org Chem 535 (2004) ASAWUM

9. Problem 2 (12 points) Consider the heterocyclic derivatives displayed on the next two slides (R = H): 2-a: Suggest most prevalent conformations for the 7-membered ring and indicate whether the predicted ring conformation is expected to be the dominant one or whether major alternative conformations are expected to co-exist (6 points) 2-b: For the dominant conformation in each case, predict the spatial arrangement of the phenyl susbtituent relative to the 7-membered ring (6 points) 2-c: Further derivatives may be planned with R = aryl (as indicated in red). In which of the 6 cases would you consider such derivatives to be of interest as potential ligands to a 3-pocket binding site, e.g., as discussed for the p53-binding site of MDM2? Give reasons. (6 points) Note: for your answers, you may use any modeling system and incorporate appropriate models with your comments, or draw proper models by either ISIS/Draw or ChemDraw and include the drawings, or include scanned hand-written sketches (pdf’s), or simply describe your solutions in words.

10. Problem 2 (continued) R = H R = aryl (phenyl) R = H R = aryl (phenyl) R = H R = aryl (phenyl)

11. Problem 2 (continued) R = H R = aryl (phenyl) R = H R = aryl (phenyl) R = H R = aryl (phenyl)

12. Problem 3 (12 points) The compound below is much too lipophilic. In order to reduce its lipophilicity significantly, several simple derivatives, shown on the next two slides, are being suggested. Which of these suggestions would you consider to be particularly promising in reducing the lipohpilicity (logP)? Give reasons (12 points)

13. Problem 3 (continued)

14. Problem 3 (continued)

15. argatroban Problem 4 (12 points) Argatroban was one of the very early compounds, designed as a peptide mimetic inhibitor of human thrombin. Its actual binding mode to thrombin was determined only many years later by X-ray crystal structure analysis of its complex with human thrombin. The experimentally observed conformation of the bound ligand (see next slide) is remarkable as it contradicts naïve assumptions originally made in the design of this inhibitor! • Comment on • the conformation of the trans-2,4-disubstituted piperidine ring; • conformational aspects of the acyclic unit linking the piperidine and the tetrahydroquinoline units; • the conformation of the tetrahydroquinoline unit relative to the linking unit; • the fact that the sulfonamide-NH donates a hydrogen bond to a protein backbone carbonyl unit(indicated by the dotted yellow line; the N lone pair is also inscribed to indicate the slightly pyramidalconfiguration at the N atom); • the fact that the SO2 group does not engage in hydrogen bonding; • do you think that this conformation is particularly enforced by the relatively rigid binding pocket of thrombin or to what extent could this bound conformation already be pre-organized in the free solution?

16. argatroban oxyanion hole 3 protein structures of human thrombin (from different thrombin-inhibitor complexes) are superimposed to indicate the relative rigidity of thrombin.

17. Problem 5 (12 points) A search in the Thomson Reuters Integrity database reveals the following 6 compounds being currently in Phase-II of clinical development (see subsequent 3 slides). They are characterized by having a di-, tri-, or even tetrasubstituted piperidine core unit. In the absence of their X-ray crystal structures, discuss for each case the likely conformation for the piperidine core unit and the arrangements of its substituents. Note: in the last two cases, discuss the likely conformation of the 7-membered ring first and then consider the conformation of the piperidine ring and its substituent(s). Note: for your answers, you may use any modeling system and incorporate appropriate models with your comments, or draw proper models by either ISIS/Draw or ChemDraw and include the drawings, or include scanned hand-written sketches (pdf’s), or simply describe your solutions in words.

18. Problem 5 (continued) by Incyte in chemotherapy of breast cancer from CCD (‘Center for Chemistry of Drugs) against heart failure/hypertension

19. Problem 5 (continued) by Takeda against sleep disorders by GlaxoSmithKline as antidepressant and against post-traumatic stress disorders

20. HOOC Problem 5 (continued) by Sanofi-Aventis against heartfailure and hypertension by Brystol-Myers Squipp against angina pectoris/heart failure