Your SlideShare is downloading. ×
0
Quantitative Structure-Activity Relationships (QSAR) <ul><li>   Attempts to identify and quantitate physicochemical prope...
Quantitative Structure-Activity Relationships (QSAR) <ul><li> dv   fewer compounds may need to be made </li></ul><ul><li...
Log P  (partition coefficient)  Hydrophobicity <ul><li> P = [drug] in octanol / [drug] in water </li></ul><ul><li>Vary lo...
Log P  (partition coefficient)  Hydrophobicity <ul><li>Plot  log 1/C vs. log P </li></ul><ul><li>  </li></ul><ul><li>Typic...
Log P:  Hydrophobicity
Log P <ul><li>Parabolic curve : </li></ul><ul><li>log 1/C = - k 1  (log P) 2   +  k 2  log P  + k3 </li></ul><ul><li>  </l...
Log P Note that one is not always measuring biological activity, sometimes binding!
*RELATIVELY FEW DRUGS EXIST WHOSE ACTIVITY IS RELATED TO LOG P ALONE!!! --those that do are the general anesthetics--parti...
Log P Values:  Uses With these equations for anesthetics (ethers only), it is possible to predict activity if log P known ...
Example:  decreased CNS side effects
P vs.   <ul><li>  </li></ul><ul><li>P measures drug’s overall hydrophobicity & measures drug’s transportability  </li></u...
 <ul><li>Possible to calculate the substituent hydrophobicity constant (  ) </li></ul><ul><li>A measure of how hydrophob...
 <ul><li> x  = log P x   - log P H </li></ul><ul><li>H is for standard compound </li></ul><ul><li>positive    = substit...
   values for various substituents on aromatic rings Theoretical Log P for chlorobenzene   = log P for benzene +    for ...
   values for various substituents on aromatic rings Theoretical Log P for meta-chlorobenzamide = log P for benzene +   ...
Tables of   <ul><li>See Table 2.5 </li></ul><ul><li>Many tables exist for all sorts of different structures.  </li></ul><...
Electronic Effects:  The Hammett Constant   Hammett constant (1940)     Measure e-withdrawing or e-donating effects  (co...
Electronic Effects:  The Hammett Constant   Electron Withdrawing Groups:  Equilibrium shifts Right & K x  > K benzoic Sin...
Electronic Effects:  The Hammett Constant     e-withdrawing groups stabilize the carboxylate ion:  larger Kx, and have po...
Hammett Constants Hammett constant  takes into account both  resonance and inductive  effects; thus, the value depends on ...
Uses Only one known example where just Hammett constants effectively predict activity (insecticides, diethyl phenyl phosph...
Steric Effects            much harder to quantitate Examples are:            Taft’s steric factor (Es)   (~1956), an exp...
Putting it all together <ul><li>For a group of antihistamines, </li></ul><ul><li>Log (1/C) = 0.440 Es – 2.204  </li></ul><...
Hansch Analysis <ul><li>Proposed that drug action could be divided into 2 stages:  1)  Transport & 2) Binding </li></ul><u...
Hansch Analysis <ul><li>Look at size and sign for each component of the equation. </li></ul><ul><li>Values of r <<0.9 indi...
Craig Plots <ul><li>Plots of one parameter against another. </li></ul><ul><li>For example,    vs.   </li></ul><ul><li>Us...
Hansch equations log 1/C = 1.22    – 1.59    + 7.89  (n=22; s=0.238; r= 0.918 log 1/C = 0.398    + 1.089    + 1.03 Es ...
 
Upcoming SlideShare
Loading in...5
×

Qsar lecture

4,533

Published on

Published in: Education, Technology, Business
1 Comment
1 Like
Statistics
Notes
No Downloads
Views
Total Views
4,533
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
178
Comments
1
Likes
1
Embeds 0
No embeds

No notes for slide

Transcript of "Qsar lecture"

  1. 1. Quantitative Structure-Activity Relationships (QSAR) <ul><li>   Attempts to identify and quantitate physicochemical properties of a drug in relation to its biological activity or binding </li></ul><ul><li>    Studies hydrophobic, electronic, and steric properties--either whole molecule or pieces </li></ul><ul><li>med chemist draws up an equation that quantifies the relationship & allows one to predict (to some extent) the biological activity </li></ul><ul><li>  </li></ul>
  2. 2. Quantitative Structure-Activity Relationships (QSAR) <ul><li> dv  fewer compounds may need to be made </li></ul><ul><li> owever  if compound does not “fit” the equation, then chemist knows they need to modify the equation </li></ul><ul><li>  </li></ul>
  3. 3. Log P (partition coefficient) Hydrophobicity <ul><li> P = [drug] in octanol / [drug] in water </li></ul><ul><li>Vary log P & see how this affects the biological activity. </li></ul><ul><li>Biological activity normally expressed as 1/C, where C = [drug] required to achieve a defined level of biological activity. The more active drugs require lower concs. </li></ul>
  4. 4. Log P (partition coefficient) Hydrophobicity <ul><li>Plot log 1/C vs. log P </li></ul><ul><li>  </li></ul><ul><li>Typically over a small range of log P, e.g . 1-4, a straight line is obtained   </li></ul><ul><li>e.g . log 1/C = 0.75 log P + 2.30 </li></ul><ul><li>If graph is extended to very high log P values, then get a parabolic curve. Reasons: </li></ul><ul><li>   poorly soluble in aqueous phase </li></ul><ul><li>   trapped in fat depots </li></ul><ul><li>more susceptible to metabolism </li></ul>
  5. 5. Log P: Hydrophobicity
  6. 6. Log P <ul><li>Parabolic curve : </li></ul><ul><li>log 1/C = - k 1 (log P) 2 + k 2 log P + k3 </li></ul><ul><li>  </li></ul><ul><li>When P small, dominated by log P term </li></ul><ul><li>When P large, log P squared dominates & so activity decreases </li></ul>
  7. 7. Log P Note that one is not always measuring biological activity, sometimes binding!
  8. 8. *RELATIVELY FEW DRUGS EXIST WHOSE ACTIVITY IS RELATED TO LOG P ALONE!!! --those that do are the general anesthetics--partition into cell membranes, & thereby affect membrane structure & nerve function --no specific drug-receptor interactions  
  9. 9. Log P Values: Uses With these equations for anesthetics (ethers only), it is possible to predict activity if log P known (doesn’t work if structure very different) ether chloroform halothane 0.98 1.97 2.3 (anesthetic activity increases in same order)   Drugs with Log P values close to 2 should be able to enter the CNS efficiently e.g . barbiturates have log P values close to 2 also; want to make sure log P value is much lower if you don’t want possible CNS side effects
  10. 10. Example: decreased CNS side effects
  11. 11. P vs.  <ul><li>  </li></ul><ul><li>P measures drug’s overall hydrophobicity & measures drug’s transportability </li></ul><ul><li>measures the hydrophobicity of a specific region on the drug--hydrophobic bonding to a receptor </li></ul><ul><li>substituent hydrophobicity constant,  </li></ul>
  12. 12.  <ul><li>Possible to calculate the substituent hydrophobicity constant (  ) </li></ul><ul><li>A measure of how hydrophobic relative to H </li></ul><ul><li>Measure P experimentally for a standard compound with and without a substituent (X). Use this equation: </li></ul><ul><li>  </li></ul><ul><li> x = log P x - log P H </li></ul>
  13. 13.  <ul><li> x = log P x - log P H </li></ul><ul><li>H is for standard compound </li></ul><ul><li>positive  = substituent more hydrophobic than H </li></ul><ul><li>negative  = less hydrophobic than H </li></ul>
  14. 14.  values for various substituents on aromatic rings Theoretical Log P for chlorobenzene = log P for benzene +  for Cl = 2.13 + 0.71 = 2.84 0.14 0.86 0.71 1.16 -1.49 -0.67 1.68 0.52 F Br Cl CF 3 CONH 2 OH t-Bu CH 3
  15. 15.  values for various substituents on aromatic rings Theoretical Log P for meta-chlorobenzamide = log P for benzene +  for Cl +  for CONH 2 = 2.13 + 0.71 - 1.49 = 1.35 0.14 0.86 0.71 1.16 -1.49 -0.67 1.68 0.52 F Br Cl CF 3 CONH 2 OH t-Bu CH 3
  16. 16. Tables of  <ul><li>See Table 2.5 </li></ul><ul><li>Many tables exist for all sorts of different structures. </li></ul><ul><li>Note that values will be different when using different solvent systems . </li></ul><ul><li>MOST QSAR equations have contribution from either P or  or both </li></ul>
  17. 17. Electronic Effects: The Hammett Constant  Hammett constant (1940)  Measure e-withdrawing or e-donating effects (compared to benzoic acid & how affected its ionization)  
  18. 18. Electronic Effects: The Hammett Constant  Electron Withdrawing Groups: Equilibrium shifts Right & K x > K benzoic Since  x = log K x – log K benzoic , then  will be positive .  x = log (K x /K benzoic )
  19. 19. Electronic Effects: The Hammett Constant    e-withdrawing groups stabilize the carboxylate ion: larger Kx, and have positive  values e.g. Cl, CN, CF 3   e-donating groups (e.g. alkyl) equilibrium shifts left (favoring unprotonated): lower Kx and negative  values  
  20. 20. Hammett Constants Hammett constant takes into account both resonance and inductive effects; thus, the value depends on whether the substituent is para or meta substituted -- ortho not measured due to steric effects In some positions only inductive effects effect & some both resonance & inductive effects play a part     aliphatic electronic substituent constants are also available
  21. 21. Uses Only one known example where just Hammett constants effectively predict activity (insecticides, diethyl phenyl phosphates. These drugs do not have to pass into or through a cell membrane to have activity). Log (1/C) = 2.282  – 0.348
  22. 22. Steric Effects           much harder to quantitate Examples are:          Taft’s steric factor (Es) (~1956), an experimental value based on rate constants          Molar refractivity (MR)-- measure of the volume occupied by an atom or group--equation includes the MW, density, and the index of refraction--          Verloop steric parameter --computer program uses bond angles, van der Waals radii, bond lengths
  23. 23. Putting it all together <ul><li>For a group of antihistamines, </li></ul><ul><li>Log (1/C) = 0.440 Es – 2.204 </li></ul><ul><li>(n=30, s=0.307, r= 0.886) </li></ul><ul><li>Log (1/C) = 2.814  - 0.223 </li></ul><ul><li>(n=30, s=0.519, r= 0.629) </li></ul><ul><li>Log (1/C) = 0.492 Es - 0.585  - 2.445 </li></ul><ul><li>(n=30, s= .301, r= 0.889) </li></ul>
  24. 24. Hansch Analysis <ul><li>Proposed that drug action could be divided into 2 stages: 1) Transport & 2) Binding </li></ul><ul><li>Log 1/C = k 1 P = k 2 P 2 + k 3  + k 4 Es + k 5 </li></ul>
  25. 25. Hansch Analysis <ul><li>Look at size and sign for each component of the equation. </li></ul><ul><li>Values of r <<0.9 indicate equation not reliable </li></ul><ul><li>Accuracy depends on using enough analogs, accuracy of data, & choice of parameters. </li></ul>
  26. 26. Craig Plots <ul><li>Plots of one parameter against another. </li></ul><ul><li>For example,  vs.  </li></ul><ul><li>Used to quickly decide which analogs to synthesize if the Hansch equation is known. </li></ul>
  27. 27. Hansch equations log 1/C = 1.22  – 1.59  + 7.89 (n=22; s=0.238; r= 0.918 log 1/C = 0.398  + 1.089  + 1.03 Es + 4.541 (n=9; r= 0.955) log C b = 0.765  = 0.540  2 + 1.505 log 1/c = 1.78  – 0.12  + 1.674
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×