Why Do Drugs Look the Way they Do?  By Wolfgang K.-D. Brill
Brill, May 2002 The Blockbusters in 2000 Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zyprexa Epogen, Procrit:
Brill, May 2002 Blockbusters 2000:  Mostly Heterocycles Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zyprexa Epo...
Brill, May 2002 The Blockbusters 2000:  Mostly Small Molecules Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zypr...
Brill, May 2002 Cyclic molecules  provide the highest density of atoms per surface,  heterocycles  the highest density of ...
Why Do Drugs Look the Way they Do?  Lets look at the Targets! Brill, May 2002
Drug Target Selection <ul><li>Genomics helps  to  identify “disease genes”  </li></ul><ul><li>Disease genes are genes whos...
Brill, May 2002 L. S. Goodman  et al. , Eds.,  Goodman and Gilman's The Pharmacological Basis of Therapeutics  (McGraw-Hil...
Brill, May 2002 Most Drugs Bind to Proteins
Drug Target Selection <ul><li>Biological relevance (often the only factor considered but  can be difficult to estimate wit...
Why Do Drugs Look the Way they Do?  How do Drugs get to their Targets! Brill, May 2002
Brill, May 2002 Drugs can be administerd in many ways They have to penetrate organ barriers and cell membranes to reach th...
Brill, May 2002 Since many targets are intracellular, cellular membranes present a severe obstacle 1 outside the cell  2 i...
Brill, May 2002 Lüllmann, H.; Mohr, K.; Ziegler, A. Taschenatlas der  P harmakologie, 3rd ed. Georg Thieme Verlag Stuttgar...
Statistical analysis of drugs, which are orally available revealed similarities of in  physicochemical properties!   Brill...
Distribution of “rule-of-5 properties” among drugs in  phase II development   Brill, May 2002 Lipinski C. A. et al.  Adv. ...
Brill, May 2002 Calculation of the polar surface area and correlation with bioavailability Bioavailability type:   r 2  (T...
Brill, May 2002 Drugs Bioavailability imposes stringent restrictions upon the chemical and physical properties of drugs  H...
Brill, May 2002 Drug-Target Interactions
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)C...
Brill, May 2002 <ul><li>H-bonds cannot lead to high binding constants because: </li></ul><ul><li>Drugs  are solvated prior...
Brill, May 2002 Hydrophobic interactions? drug poorly solvated by water alignment with target surface water does not bind ...
Brill, May 2002 Mostly Hydrophobic Interactions:  ATP complements its binding site in CDK2 Eksterowicz, John E. et al.  J....
Example for hydrophobic interactions in nature: Brill, May 2002 Multiple   -stacking of aromatics in a telomerase complex...
Brill, May 2002 Mostly hydrophobic interactions:  Staurosporine binds CDK2 Noble, M. E. M. et al.  Pharmacol. Ther.   82  ...
Brill, May 2002 Contributions of functional groups to binding  Andrews, P. R.  et al.  J. Med.  Chem.   27  ( 1984 ) 1648-...
Brill, May 2002 X R R Fixation of  functional  groups in space H Alignment with target surface C  - Interactions H H-bond...
Brill, May 2002 The interactions of a kinase inhibitor with the interior of a binding pocket Gray, N .  S.  et al.  Scienc...
Brill, May 2002 How drugs bind to proteins <ul><li>Large drug molecule </li></ul><ul><li>Difficult to synthesize </li></ul...
<ul><li>Large drug molecule </li></ul><ul><li>Difficult to synthesize </li></ul><ul><li>Poor passive uptake </li></ul><ul>...
Brill, May 2002 All proteins Proteins with  deep  hydrophobic pockets Proteins binding to rule - of - 5 compounds All comp...
Drug Target Selection Only proteins with deep hydrophobic pockets are suitable for low MWt. Ligands... Brill, May 2002 ......
Brill, May 2002 One type of protein requiring  the nucleotide cofactor ATP are protein tyrosine kinases <ul><li>They are <...
Brill, May 2002 Blume-Jensen, P . et al. Nature (London, U. K.)  ( 2001 )   411, 355-365  Various receptors with kinase-do...
Brill, May 2002 Kinase mechanism
Brill, May 2002 Hydrophobic pockets within ATP-binding domains Traxler, P. et. al.  Pharmacol. Ther.   82  ( 1999 ) 195-206
Why  D o Drugs Look the Way they Do?  Heterocycles provide opportunities for designing functional group isoster e s Brill,...
Brill, May 2002 <ul><li>Bioisosteres for phenyl and phenol residues </li></ul><ul><ul><li>To improve solubility  </li></ul...
Brill, May 2002 Bioisosters for carboxylic acid derivatives
Brill, May 2002 Why are many drugs aromatics? Comparison of two compounds C 8 H 8 : Which has the greater surface?
Why  D o Drugs Look the Way they Do?  Brill, May 2002 <ul><li>Drugs are small molecules with some hydrophobicity to be  bi...
Why  D o Drugs Look the Way they Do?  Brill, May 2002 <ul><li>Drugs are small molecules with some hydrophobicity to be  bi...
Acknowledgement Brill, May 2002 Dr. Jean-Yves Trosset
Upcoming SlideShare
Loading in …5
×

Why Do Drugs Look The Way They Do

803 views

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
803
On SlideShare
0
From Embeds
0
Number of Embeds
12
Actions
Shares
0
Downloads
5
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Why Do Drugs Look The Way They Do

  1. 1. Why Do Drugs Look the Way they Do? By Wolfgang K.-D. Brill
  2. 2. Brill, May 2002 The Blockbusters in 2000 Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zyprexa Epogen, Procrit:
  3. 3. Brill, May 2002 Blockbusters 2000: Mostly Heterocycles Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zyprexa Epogen, Procrit:
  4. 4. Brill, May 2002 The Blockbusters 2000: Mostly Small Molecules Prilosec Prevacid Lipidor Zocor Prozac Celebrex Zoloft Zyprexa Epogen, Procrit:
  5. 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. 6. Why Do Drugs Look the Way they Do? Lets look at the Targets! Brill, May 2002
  7. 7. Drug Target Selection <ul><li>Genomics helps to identify “disease genes” </li></ul><ul><li>Disease genes are genes whose products are directly or indirectly responsible for a disease </li></ul><ul><li>When products of a “disease gene” are not suitable targets other proteins linked via physiological or pathophysiological pathways may be. </li></ul><ul><li>About 5000-10000 targets my be suitable for drug intervention </li></ul><ul><li> Drews, J. Science (Washington, D. C.) 287 ( 2000 ) 1960-1963 . </li></ul>Brill, May 2002
  8. 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. 9. Brill, May 2002 Most Drugs Bind to Proteins
  10. 10. Drug Target Selection <ul><li>Biological relevance (often the only factor considered but can be difficult to estimate without a drug) </li></ul><ul><li>Kinetics for the endogenous process </li></ul><ul><li>Selectivity of action </li></ul><ul><li>The structure of the drug target and its suitability for interaction with low M. Wt. ligands </li></ul>Brill, May 2002
  11. 11. Why Do Drugs Look the Way they Do? How do Drugs get to their Targets! Brill, May 2002
  12. 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. 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. 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
  15. 15. Statistical analysis of drugs, which are orally available revealed similarities of in physicochemical properties! Brill, May 2002 <ul><li>Number of H-bond donors </li></ul><ul><li>(NH and OH): 0 - 5 </li></ul><ul><li>Number of H-acceptors (N: and O:): 5 - 10 </li></ul><ul><li>LogP: -2 - 5 </li></ul><ul><li>Molecular weight: 200 - 500 </li></ul><ul><li>No of rotatable bonds: </li></ul><ul><li>Formal charge: -2 - 2 </li></ul><ul><li>Number of non-hydrogens: 20 - 50 </li></ul><ul><li>Polar surface area: < 99 </li></ul>original Lipinski rule or rule-of-5
  16. 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. 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. 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. 19. Brill, May 2002 Drug-Target Interactions
  20. 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 + +
  21. 21. Brill, May 2002 <ul><li>H-bonds cannot lead to high binding constants because: </li></ul><ul><li>Drugs are solvated prior to entering the target </li></ul><ul><li>The water binding to the drug has to be replaced by the target </li></ul><ul><li>The hydrogen bond on the target has to be significantly stronger than that of the drug with water </li></ul><ul><li>In order to obtain high binding many H-bonds are necessary </li></ul><ul><li>A compound with that many H-bonds is too polar for </li></ul><ul><li>passive uptake </li></ul>
  22. 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. 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. 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. 25. Brill, May 2002 Mostly hydrophobic interactions: Staurosporine binds CDK2 Noble, M. E. M. et al. Pharmacol. Ther. 82 ( 1999 ) 269-278
  26. 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. 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. 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
  29. 29. Brill, May 2002 How drugs bind to proteins <ul><li>Large drug molecule </li></ul><ul><li>Difficult to synthesize </li></ul><ul><li>Poor passive uptake </li></ul><ul><li>Hydrophilic (for solubility) </li></ul>+ <ul><li>Flat, hydrophillic protein surface </li></ul>Only large molecules can bind to shallow surface ! <ul><li>Small drug molecule </li></ul><ul><li>Easy to synthesize </li></ul><ul><li>bioavailable </li></ul>+ Protein surface <ul><li>Poorly hydrated </li></ul><ul><li>Stressed due to hydrophobic collaps </li></ul>Small molecule can bind to deep fold!
  30. 30. <ul><li>Large drug molecule </li></ul><ul><li>Difficult to synthesize </li></ul><ul><li>Poor passive uptake </li></ul><ul><li>Hydrophilic (for solubility) </li></ul>Brill, May 2002 + <ul><li>Flat, hydrophillic protein surface </li></ul>Only large molecules can bind to shallow surface ! <ul><li>Small drug molecule </li></ul><ul><li>Easy to synthesize </li></ul><ul><li>bioavailable </li></ul>+ Protein surface <ul><li>Poorly hydrated </li></ul><ul><li>Stressed due to hydrophobic collaps </li></ul>Small molecule can bind to deep fold! How drugs bind to proteins
  31. 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. 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
  33. 33. Brill, May 2002 One type of protein requiring the nucleotide cofactor ATP are protein tyrosine kinases <ul><li>They are </li></ul><ul><li>involved in the regulation of cellular processes via substrate phosphorylation </li></ul><ul><li>Dysfunction of those processes lead to many diseases such as cancer </li></ul><ul><li>Cofactors can readily diffuse in and out of binding sites! </li></ul><ul><li>Binding sites are not optimized toward very tight binding: </li></ul><ul><li>competitive inhibition possible! </li></ul><ul><li>There are many different binding pockets for cofactors: </li></ul><ul><li>selective binding possible! </li></ul>
  34. 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. 35. Brill, May 2002 Kinase mechanism
  36. 36. Brill, May 2002 Hydrophobic pockets within ATP-binding domains Traxler, P. et. al. Pharmacol. Ther. 82 ( 1999 ) 195-206
  37. 37. Why D o Drugs Look the Way they Do? Heterocycles provide opportunities for designing functional group isoster e s Brill, May 2002 <ul><li>Improve bioavailability </li></ul><ul><li>Improve activity </li></ul><ul><li>Reduce side effects </li></ul><ul><li>Reduce toxicity </li></ul><ul><li>Circumvent patents </li></ul><ul><li>Design new chemical entities </li></ul>
  38. 38. Brill, May 2002 <ul><li>Bioisosteres for phenyl and phenol residues </li></ul><ul><ul><li>To improve solubility </li></ul></ul><ul><ul><li>To reduce toxicity </li></ul></ul>
  39. 39. Brill, May 2002 Bioisosters for carboxylic acid derivatives
  40. 40. Brill, May 2002 Why are many drugs aromatics? Comparison of two compounds C 8 H 8 : Which has the greater surface?
  41. 41. Why D o Drugs Look the Way they Do? Brill, May 2002 <ul><li>Drugs are small molecules with some hydrophobicity to be bioavailable. </li></ul><ul><li>Small molecules can only bind to proteins with deep hydrophobic pockets or folds. </li></ul><ul><li>To bind to such folds a drug must complement the inner surface of the hydrophobic pocket or fold. </li></ul><ul><li>This requires the highest possible density of funct ion ality per drug surface preoriented in space. </li></ul><ul><li>This can best be achieved with heterocycles being aromatic or with heterocycles in conjunction with other aromatic systems. </li></ul><ul><li>Heterocycles provide many facile and rapid ways for derivatizations. </li></ul>
  42. 42. Why D o Drugs Look the Way they Do? Brill, May 2002 <ul><li>Drugs are small molecules with some hydrophobicity to be bioavailable. </li></ul><ul><li>Small molecules can only bind to proteins with deep hydrophobic pockets or folds. </li></ul><ul><li>To bind to such folds a drug must complement the inner surface of the hydrophobic pocket or fold. </li></ul><ul><li>This requires the highest possible density of funct ion ality per drug surface preoriented in space. </li></ul><ul><li>This can best be achieved with heterocycles being aromatic or with heterocycles in conjunction with other aromatic systems. </li></ul><ul><li>Heterocycles provide many facile and rapid ways for derivatizations. </li></ul>
  43. 43. Acknowledgement Brill, May 2002 Dr. Jean-Yves Trosset

×