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Quantitative Structure-Activity Relationships (QSAR)

Quantitative Structure-Activity Relationships (QSAR). ·  Attempts to identify and quantitate physicochemical properties of a drug in relation to its biological activity or binding ·   Studies hydrophobic, electronic, and steric properties--either whole molecule or pieces

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Quantitative Structure-Activity Relationships (QSAR)

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  1. Quantitative Structure-Activity Relationships (QSAR) • · Attempts to identify and quantitate physicochemical properties of a drug in relation to its biological activity or binding ·  Studies hydrophobic, electronic, and steric properties--either whole molecule or pieces med chemist draws up an equation that quantifies the relationship & allows one to predict (to some extent) the biological activity

  2. Quantitative Structure-Activity Relationships (QSAR) • Adv: fewer compounds may need to be made • However, if compound does not “fit” the equation, then chemist knows they need to modify the equation

  3. Log P (partition coefficient) Hydrophobicity • ·P = [drug] in octanol / [drug] in water • Vary log P & see how this affects the biological activity. • 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.

  4. Log P (partition coefficient) Hydrophobicity • Plot log 1/C vs. log P • Typically over a small range of log P, e.g. 1-4, a straight line is obtained   e.g. log 1/C = 0.75 log P + 2.30 • If graph is extended to very high log P values, then get a parabolic curve. Reasons: • · poorly soluble in aqueous phase • ·  trapped in fat depots • more susceptible to metabolism

  5. Log P: Hydrophobicity

  6. Log P • Parabolic curve: • log 1/C = - k1 (log P)2 + k2 log P + k3 • When P small, dominated by log P term • When P large, log P squared dominates & so activity decreases

  7. Log P Note that one is not always measuring biological activity, sometimes binding!

  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. 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. Example: decreased CNS side effects

  11. P vs. p • P measures drug’s overall hydrophobicity & measures drug’s transportability • measures the hydrophobicity of a specific region on the drug--hydrophobic bonding to a receptor substituent hydrophobicity constant, p

  12. p • Possible to calculate the substituent hydrophobicity constant (p) • A measure of how hydrophobic relative to H • Measure P experimentally for a standard compound with and without a substituent (X). Use this equation: px = log Px - log PH

  13. p • px = log Px - log PH • H is for standard compound • positive p = substituent more hydrophobic than H • negative p = less hydrophobic than H

  14. p values for various substituents on aromatic rings Theoretical Log P for chlorobenzene = log P for benzene + p for Cl = 2.13 + 0.71 = 2.84

  15. p values for various substituents on aromatic rings Theoretical Log P for meta-chlorobenzamide = log P for benzene + p for Cl + p for CONH2 = 2.13 + 0.71 - 1.49 = 1.35

  16. Tables of p • See Table 2.5 • Many tables exist for all sorts of different structures. • Note that values will be different when using different solvent systems. • MOST QSAR equations have contribution from either P or p or both

  17. Electronic Effects: The Hammett Constant s Hammett constant (1940) s Measure e-withdrawing or e-donating effects (compared to benzoic acid & how affected its ionization)

  18. Electronic Effects: The Hammett Constant s Electron Withdrawing Groups: Equilibrium shifts Right & Kx > Kbenzoic Since sx = log Kx – log Kbenzoic, then s will be positive . sx = log (Kx/Kbenzoic)

  19. Electronic Effects: The Hammett Constant s e-withdrawing groups stabilize the carboxylate ion: larger Kx, and have positive s values e.g. Cl, CN, CF3 e-donating groups (e.g. alkyl) equilibrium shifts left (favoring unprotonated): lower Kx and negative s values

  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. 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 s – 0.348

  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. Putting it all together For a group of antihistamines, Log (1/C) = 0.440 Es – 2.204 (n=30, s=0.307, r= 0.886) Log (1/C) = 2.814 s - 0.223 (n=30, s=0.519, r= 0.629) Log (1/C) = 0.492 Es - 0.585 s - 2.445 (n=30, s= .301, r= 0.889)

  24. Hansch Analysis • Proposed that drug action could be divided into 2 stages: 1) Transport & 2) Binding • Log 1/C = k1P = k2P2 + k3s + k4Es + k5

  25. Hansch Analysis • Look at size and sign for each component of the equation. • Values of r <<0.9 indicate equation not reliable • Accuracy depends on using enough analogs, accuracy of data, & choice of parameters.

  26. Craig Plots • Plots of one parameter against another. • For example, p vs. s • Used to quickly decide which analogs to synthesize if the Hansch equation is known.

  27. Hansch equations log 1/C = 1.22 p – 1.59 s + 7.89 (n=22; s=0.238; r= 0.918 log 1/C = 0.398 p + 1.089 s + 1.03 Es + 4.541 (n=9; r= 0.955) log Cb = 0.765 p = 0.540 p2 + 1.505 log 1/c = 1.78 p – 0.12 s + 1.674

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