1. Why Do Drugs Look the Way they Do? By Wolfgang K.-D. Brill

2. Brill, May 2002 The Blockbusters in 2000 Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zyprexa Epogen, Procrit:

3. Brill, May 2002 Blockbusters 2000: Mostly Heterocycles Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zyprexa Epogen, Procrit:

4. Brill, May 2002 The Blockbusters 2000: Mostly Small Molecules Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zyprexa Epogen, Procrit:

5. Brill, May 2002 Cyclic molecules provide the highest density of atoms per surface, heterocycles the highest density of chemical functionalities with well-defined orientation in space per surface. X R R Various functional groups H Hydrophobic residues C  - electron clouds H Polar residues

6. Why Do Drugs Look the Way they Do? Lets look at the Targets! Brill, May 2002

8. Brill, May 2002 L. S. Goodman et al. , Eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics (McGraw-Hill, New York, ed. 9, 1996).

9. Brill, May 2002 Most Drugs Bind to Proteins

11. Why Do Drugs Look the Way they Do? How do Drugs get to their Targets! Brill, May 2002

12. Brill, May 2002 Drugs can be administerd in many ways They have to penetrate organ barriers and cell membranes to reach their target

13. Brill, May 2002 Since many targets are intracellular, cellular membranes present a severe obstacle 1 outside the cell 2 inside the cell 3 freeze fracture passes through the middle bilayer protein 4,5,7,8, 9 integral membrane proteins 6,11 peripheral membrane proteins 10 carbohydrate residues Singer, S. J.; Nicolson, G. L. Science (Washington, D. C.) 175 ( 1972 ) 723

14. Brill, May 2002 Lüllmann, H.; Mohr, K.; Ziegler, A. Taschenatlas der P harmakologie, 3rd ed. Georg Thieme Verlag Stuttgart, New York 1996 Transport of drugs Passive diffusion rule of 5 obligatory Active transport drugs use systems for: amino acids L-DOPA basic polypeptides amino glycosides Receptor mediated transport 1,2: binding to receptor 3: adaptin addition 4: accumulation of receptors 5: formation of vesicle 6-8: formation of endosome and recycling of receptor 9: intracellular distribution via endosome vesicular transport out out in

16. Distribution of “rule-of-5 properties” among drugs in phase II development Brill, May 2002 Lipinski C. A. et al. Adv. Drug Delivery Rev. 23 ( 1997 ) 3-25

17. Brill, May 2002 Calculation of the polar surface area and correlation with bioavailability Bioavailability type: r 2 (TPSA) Oral drug absorption: 0.91 Caco-2-permeabilty: 0.56-0.96 Blood brain barrier: 0.66-0.84 Human jejunum permeability: 0.75 Ertl et al. J. Med. Chem. 43 ( 2000 ) 3714-3717

18. Brill, May 2002 Drugs Bioavailability imposes stringent restrictions upon the chemical and physical properties of drugs How can the drug-like compounds interact with proteins? All compounds Rule - of - 5 compounds

19. Brill, May 2002 Drug-Target Interactions

20. Brill, May 2002 H-bonds ? HOH ........ OH 2 - 6.4 Kcal mol -1 H 2 O ........ HSCH 3 - 3.2 Kcal mol -1 HOH ........ S(H)CH 3 - 3.1 Kcal mol -1 Imidazolinium/water - 14.0 Kcal mol -1 CH 3 CO 2 - ....... HOH - 19.0 Kcal mol -1  S int  H DW  S rt  S vib  H DR  RW  S W + +

22. Brill, May 2002 Hydrophobic interactions? drug poorly solvated by water alignment with target surface water does not bind well to target site: can readily be displaced

23. Brill, May 2002 Mostly Hydrophobic Interactions: ATP complements its binding site in CDK2 Eksterowicz, John E. et al. J. Mol. Graphics & Modelling 20 ( 2002 ) 469-477.

24. Example for hydrophobic interactions in nature: Brill, May 2002 Multiple  -stacking of aromatics in a telomerase complex Horvath, M. P. et al. Cell 95 ( 1998 ) 963-974

25. Brill, May 2002 Mostly hydrophobic interactions: Staurosporine binds CDK2 Noble, M. E. M. et al. Pharmacol. Ther. 82 ( 1999 ) 269-278

26. Brill, May 2002 Contributions of functional groups to binding Andrews, P. R. et al. J. Med. Chem. 27 ( 1984 ) 1648-1657 DOF -0.7 -0.7- -1.0 C(sp 2 ) 0.7 0.6- 0.8 C(sp 3 ) 0.8 0.1- 1.0 N + 11.5 11.4- 15.0 N 1.2 0.8- 1.8 CO 2 - 8.2 7.3- 10.3 OPO 3 - 10.0 7.7- 10.6 OH 2.5 2.5- 4.0 C=O 3.4 3.2- 4.0 O,S 1.1 0.7- 2.0 halogen 1.3 0.2- 2.0 Group Energy range over (Kcalmol -1 ) 200 cpds. DOF: degrees of freedom

27. Brill, May 2002 X R R Fixation of functional groups in space H Alignment with target surface C  - Interactions H H-bond The greater the surface of a drug involved in interactions with its target, the greater the binding!

28. Brill, May 2002 The interactions of a kinase inhibitor with the interior of a binding pocket Gray, N . S. et al. Science (Washington, D. C.) 281 ( 1998 ) 533-538

31. Brill, May 2002 All proteins Proteins with deep hydrophobic pockets Proteins binding to rule - of - 5 compounds All compounds Rule - of 5 compounds Targets Drugs

32. Drug Target Selection Only proteins with deep hydrophobic pockets are suitable for low MWt. Ligands... Brill, May 2002 ...such as proteins binding nucleotide cofactors

34. Brill, May 2002 Blume-Jensen, P . et al. Nature (London, U. K.) ( 2001 ) 411, 355-365 Various receptors with kinase-domains intracellular extracellular kinase domain

35. Brill, May 2002 Kinase mechanism

36. Brill, May 2002 Hydrophobic pockets within ATP-binding domains Traxler, P. et. al. Pharmacol. Ther. 82 ( 1999 ) 195-206

39. Brill, May 2002 Bioisosters for carboxylic acid derivatives

40. Brill, May 2002 Why are many drugs aromatics? Comparison of two compounds C 8 H 8 : Which has the greater surface?

43. Acknowledgement Brill, May 2002 Dr. Jean-Yves Trosset