Medicinal Chemistry Lecture 5
<ul><li>SARs  and QSARs </li></ul>
Continue…
 
 
 
Changing the Existing Substituent of a Lead <ul><li>Is often made with the use of isosteres concept </li></ul><ul><li>Isos...
Classical Isosteres and Bioisosteres
 
Quantitative Structure-Activity  Relationships (QSARs) <ul><li>Attempt to remove the element of luck from drug design </li...
<ul><li>It is possible to either measure or calculate these parameters for a large number of compounds and relate their va...
Regression Analysis <ul><li>A group of mathematical methods used to obtain mathematical equations relating different sets ...
 
<ul><li>Using statistical data from other compounds, a theoretical value for x parameter for an as yet unsynthesized drug ...
<ul><li>The main properties that affect the activity of the molecule are: </li></ul><ul><li>Lipoliphicity  </li></ul><ul><...
Lipophilicity <ul><li>Measure of the drug solubility in the lipid membrane </li></ul><ul><li>Determines how easily the dru...
Electronic effects <ul><li>Of the groups within the molecule will affects its electronic distribution. </li></ul><ul><li>E...
Steric Effects <ul><li>Drug size and shape will determine whether the drug molecule will be able to get close enough to th...
QSAR Equations <ul><li>Usually take the form: </li></ul>
<ul><li>In these equations, activity is normally expressed as: </li></ul><ul><li>Log [1/(concentration term)], usually  C,...
<ul><li>QSAR studies are normally carried out on a series of structurally similar compounds. </li></ul><ul><li>They can al...
Lipophilicity <ul><li>Partition coefficient is used along with another parameter ( π ) to represent lipophilicity. </li></...
<ul><li>The nature of the relationship between  P  and drug activity depends on the range of  P  values obtained for the d...
<ul><li>Over larger ranges of  P  values the graph of log 1/ C  against log  P  often has a parabolic form with a maximum ...
<ul><li>The existence of this maximum value implies that there is a balance between aqueous and lipid solubility for maxim...
<ul><li>Hansch found that these parabolic relationships could be represented reasonably accurately by equations of this fo...
Lipophilic Substituent Constants  π <ul><li>Also known as hydrophobic substituent constants </li></ul><ul><li>They represe...
<ul><li>Where  P RH  and  P Rx  are the partition coefficients of the standard compound and its monosubstituted analogue r...
<ul><li>Positive  π  value means that the substituent has a higher lipophilicity than hydrogen and so will probably will i...
 
<ul><li>Lipophilic constants are frequently used when dealing with a series of analogues in which only the substituents ar...
Next Lecture <ul><li>Electronic Parameters </li></ul><ul><li>Steric Parameters </li></ul><ul><li>Receptors and Receptor Si...
<ul><li>The End </li></ul>
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Lecture 5

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Lecture 5

  1. 1. Medicinal Chemistry Lecture 5
  2. 2. <ul><li>SARs and QSARs </li></ul>
  3. 3. Continue…
  4. 7. Changing the Existing Substituent of a Lead <ul><li>Is often made with the use of isosteres concept </li></ul><ul><li>Isosteres are groups that exhibits some similarities in their chemical and/or physical properties. </li></ul><ul><li>As a result they may exhibit similar pharmacokinetic and pharmacodynamic properties. </li></ul><ul><li>I.e. the replacement of a substituent by its isostere is more likely to result in the formation of an analogue with the same type of bioactivity as the lead than the totally random selection of an alternative substituent. </li></ul>
  5. 8. Classical Isosteres and Bioisosteres
  6. 10. Quantitative Structure-Activity Relationships (QSARs) <ul><li>Attempt to remove the element of luck from drug design </li></ul><ul><li>Establishing mathematical relationships in the form of equations between biological activity and measurable physicochemical parameters. </li></ul><ul><li>Parameters represent properties such as lipophilicity, shape and size of drugs. </li></ul><ul><li>They are always defined as numbers that are derived from practical data that is related to the property that the parameter represents </li></ul>
  7. 11. <ul><li>It is possible to either measure or calculate these parameters for a large number of compounds and relate their values to the biological activity by means of mathematical equations using statistical methods (e. g regression analysis). </li></ul><ul><li>These equations can be used to make informed choices about what drug analogue to synthesize. </li></ul>
  8. 12. Regression Analysis <ul><li>A group of mathematical methods used to obtain mathematical equations relating different sets of data that have been obtained from experimental work or calculated using theoretical considerations. </li></ul><ul><li>Data are fed into suitable computer program, which on execution, produces an equation that represent the line that is the best fit for those data. </li></ul>
  9. 14. <ul><li>Using statistical data from other compounds, a theoretical value for x parameter for an as yet unsynthesized drug can be calculated. </li></ul><ul><li>Substituting this value in the appropriate equation relating activity to the parameter makes it possible to calculate the theoretical activity of the unsynthesized compound. </li></ul><ul><li>Alternatively, the equation can be used to determine the value x for the parameter y that would give optimum activity. </li></ul><ul><li>As a result only the analogues that will give the value of y at the region of x need to be prepared. </li></ul>
  10. 15. <ul><li>The main properties that affect the activity of the molecule are: </li></ul><ul><li>Lipoliphicity </li></ul><ul><li>Electronic Effects within the molecule </li></ul><ul><li>Size and shape of the molecule (steric effects) </li></ul>
  11. 16. Lipophilicity <ul><li>Measure of the drug solubility in the lipid membrane </li></ul><ul><li>Determines how easily the drug passes through the lipid membrane. </li></ul><ul><li>Partition coefficient is the main parameter used to represent lipophilicity </li></ul>
  12. 17. Electronic effects <ul><li>Of the groups within the molecule will affects its electronic distribution. </li></ul><ul><li>Electronic distribution has a direct bearing on how easily and permanently the drug will bind to the receptor </li></ul><ul><li>Hammet ð constant is used to represent electronic effects </li></ul>
  13. 18. Steric Effects <ul><li>Drug size and shape will determine whether the drug molecule will be able to get close enough to the target site in order to bind to it. </li></ul><ul><li>Are represented by Taft’s Ms steric constants </li></ul>
  14. 19. QSAR Equations <ul><li>Usually take the form: </li></ul>
  15. 20. <ul><li>In these equations, activity is normally expressed as: </li></ul><ul><li>Log [1/(concentration term)], usually C, the minimum concentration required to cause a defined biological response. </li></ul><ul><li>When the correlation between the parameter and the activity is not strong, other parameters must be playing an important role and therefore must be incorporated in the QSAR equation. </li></ul>
  16. 21. <ul><li>QSAR studies are normally carried out on a series of structurally similar compounds. </li></ul><ul><li>They can also be carried out on diverse set of compounds </li></ul><ul><li>In each case, the widest range of parameters must be considered </li></ul>
  17. 22. Lipophilicity <ul><li>Partition coefficient is used along with another parameter ( π ) to represent lipophilicity. </li></ul><ul><li>Partition coefficient is used for the whole molecule while π is related to substituent groups </li></ul>
  18. 23. <ul><li>The nature of the relationship between P and drug activity depends on the range of P values obtained for the drugs used. </li></ul><ul><li>If the range is small the results may be expressed as a straight line equation having the formula below in which K 1 and K 2 are constants: </li></ul>
  19. 24. <ul><li>Over larger ranges of P values the graph of log 1/ C against log P often has a parabolic form with a maximum value (log P˚ ). </li></ul>
  20. 25. <ul><li>The existence of this maximum value implies that there is a balance between aqueous and lipid solubility for maximum biological activity. </li></ul><ul><li>Below P˚ the drug will be reluctant to enter the membrane whilst above P˚ the drug will be reluctant to leave the membrane. </li></ul><ul><li>Log P˚ represent the optimum partition coefficient for biological activity </li></ul>
  21. 26. <ul><li>Hansch found that these parabolic relationships could be represented reasonably accurately by equations of this form (where K 1 , K 2 , and K 3 are constants that are normally determined by regression analysis): </li></ul>
  22. 27. Lipophilic Substituent Constants π <ul><li>Also known as hydrophobic substituent constants </li></ul><ul><li>They represent the contribution that a group make to the partition coefficient and were defined by Hansch and his coworkers as : </li></ul>
  23. 28. <ul><li>Where P RH and P Rx are the partition coefficients of the standard compound and its monosubstituted analogue respectively. </li></ul><ul><li>When many substituents are present, π of the compound is the sum of π values for all the substituents. </li></ul><ul><li>The value of π for each substituent will vary with the structural environment of that substituent </li></ul><ul><li>This value will also depend on the solvent system used in the determination of the partition coefficient value </li></ul><ul><li>Consequently, average values or the values relevant to the type of structure being investigated may be used in the determination of the activity relationship. </li></ul>
  24. 29. <ul><li>Positive π value means that the substituent has a higher lipophilicity than hydrogen and so will probably will increase the concentration of the drug in the organic phase and by inference its concentration in the membrane of the the biological system. </li></ul><ul><li>Negative π values means that the substituent has a lower lipophilicity than hydrogen and so will probably increase the concentration of the drug in the aqueous phase and by inference its concentration in the aqueous media of the biological systems </li></ul>
  25. 31. <ul><li>Lipophilic constants are frequently used when dealing with a series of analogues in which only the substituents are different </li></ul><ul><li>This usage is based on the assumption that the lipophilic effect of the unchanged part of the structure is similar for each of the analogues. </li></ul>
  26. 32. Next Lecture <ul><li>Electronic Parameters </li></ul><ul><li>Steric Parameters </li></ul><ul><li>Receptors and Receptor Sites </li></ul>
  27. 33. <ul><li>The End </li></ul>

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