![Hydrophobicity of the Molecule
Partition Coefficient P = [Drug in octanol]
[Drug in water]
High P High hydrophobicity
•Activity of drugs is often related to P
e.g. binding of drugs to serum albumin
(straight line - limited range of log P)
Log (1/C)
Log P
. .
.
.. .
. ..
0.78 3.82
Log 1
C
= 0.75 logP + 2.30
•Binding increases as log P increases
•Binding is greater for hydrophobic drugs
13](https://image.slidesharecdn.com/quantitativestructureactivityrelationship-180309085920/85/Quantitative-structure-activity-relationship-QSAR-13-320.jpg)
![Electronic Effects
Hammett Substituent Constant (s)
Notes:
•The constant (s) is a measure of the e-withdrawing or e-donating influence of
substituents
•It can be measured experimentally and tabulated
(e.g. s for aromatic substituents is measured by comparing the
dissociation constants of substituted benzoic acids with benzoic acid)
X=H K H = Dissociation constant= [PhCO 2-]
[PhCO 2H]
+CO2H CO2 H
X X
16](https://image.slidesharecdn.com/quantitativestructureactivityrelationship-180309085920/85/Quantitative-structure-activity-relationship-QSAR-16-320.jpg)
Quantitative structure - activity relationship (QSAR)
- 2. 2
- 3. The number of compounds required for synthesis in order to place 10 different groups in 4 positions of benzene ring is 104 Solution: synthesize a small number of compounds and from their data derive rules to predict the biological activity of other compounds. 3
- 4. QSAR what actually do? IDENTIFY AND QUANTIFY the Physico-chemical properties effect on Drug’s Biological activity Such relationships holds – Equations can be drawn up- some confidence to which should be Fit to the target PHARMACOKIINETICS 4
- 5. QSAR and Drug Design Compounds + biological activity New compounds with improved biological activity QSAR 5
- 6. Instead of trial and error , use computer to help Now desired structure can be designed computationally PROCEDURE 6
- 7. HOW it is LOOK LIKE7
- 8. PHYSICO-CHEMICAL PROPERTIES - log 10P (X axis) BIOLOGICAL ACITIVITY - log1/C (Y axis) “Linear regression analysis by the least Squares method” Draw a line through the data points most of the points will be scattered on the either side of the line is best Best line through the points will be the line where this total sum of squares is minimum y=mx+c M,C are variaents determaines the line each time for every n number of compounds using relevant softwares8
- 9. 2.Correlation graph analyse To see if the relationship is meaningful. figures statistical evidence obtained to support QSAR equation and Quantifies the goodness to fit Regression coefficient (r) is the measure of How well the eqn explains the varience in activity observed Sscalc – measure of how much the experimental activity of the compound varies from calculated Ssmean –how much experimental activities varies from mean of all experimental activities R=1 perfect fit 9
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- 11. Drug and Target interactions 11
- 12. ConceptsOF DESCRIPTORS •Aims To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula •Requirements Quantitative measurements for biological and physicochemical properties •Physicochemical Properties •Hydrophobicity of the molecule •Hydrophobicity of substituents •Electronic properties of substituents •Steric properties of substituents Most common properties studied 12
- 13. Hydrophobicity of the Molecule Partition Coefficient P = [Drug in octanol] [Drug in water] High P High hydrophobicity •Activity of drugs is often related to P e.g. binding of drugs to serum albumin (straight line - limited range of log P) Log (1/C) Log P . . . .. . . .. 0.78 3.82 Log 1 C = 0.75 logP + 2.30 •Binding increases as log P increases •Binding is greater for hydrophobic drugs 13
- 14. Example 2 General anaesthetic activity of ethers (parabolic curve - larger range of log P values) Optimum value of log P for anaesthetic activity = log Po Log 1 C = -0.22(logP)2 + 1.04 logP + 2.16 Log P o Log P Log (1/C) Hydrophobicity of Substituents Benzene (Log P = 2.13) Chlorobenzene (Log P = 2.84) Benzamide (Log P = 0.64) cll CONH2 14
- 15. QSAR equations are only applicable to compounds in the same structural class (e.g. ethers) •However, log Po is similar for anaesthetics of different structural classes (ca. 2.3) •Structures with log P ca. 2.3 enter the CNS easily (e.g. potent barbiturates have a log P of approximately 2.0) •Can alter log P value of drugs away from 2.0 to avoid CNS side effects Hydrophobicity Notes: 15
- 16. Electronic Effects Hammett Substituent Constant (s) Notes: •The constant (s) is a measure of the e-withdrawing or e-donating influence of substituents •It can be measured experimentally and tabulated (e.g. s for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid) X=H K H = Dissociation constant= [PhCO 2-] [PhCO 2H] +CO2H CO2 H X X 16
- 17. + X = electron withdrawing group X CO2CO2H X H X= electron withdrawing group (e.g. NO2) s X = log K X K H = logK X - logK H Charge is stabilised by X Equilibrium shifts to right KX > KH Positive value Hammett Substituent Constant (s) 17
- 18. X= electron donating group (e.g. CH3) s X = log K X K H = logK X - logK H Charge destabilised Equilibrium shifts to left KX < KH Negative value Hammett Substituent Constant (s) + X = electron withdrawing group X CO2CO2H X H 18
- 19. NOTES: s value depends on inductive and resonance effects s value depends on whether the substituent is meta or para ortho values are invalid due to steric factors Hammett Substituent Constant (s) 19
- 20. QSAR Equation: Diethylphenylphosphates (Insecticides) log 1 C = 2.282s - 0.348 Conclusion: e-withdrawing substituents increase activity Hammett Substituent Constant (s) X O P O OEt OEt 20
- 21. Aliphatic electronic substituents •Defined by sI •Purely inductive effects •Obtained experimentally by measuring the rates of hydrolyses of aliphatic esters •Hydrolysis rates measured under basic and acidic conditions X= electron donating Rate sI = -ve X= electron withdrawing Rate sI = +ve Basic conditions: Rate affected by steric + electronic factors Gives sI after correction for steric effect Acidic conditions: Rate affected by steric factors only (see Es) + Hydrolysis HOMe CH2 OMe C O X CH2 OH C O X 21
- 22. Steric Factors Verloop Steric Parameter - calculated by software (STERIMOL) - gives dimensions of a substituent - can be used for any substituent L B 3 B 4 B4 B3 B2 B1 C O O H H O C O Example - Carboxylic acid 22
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- 24. 3D-QSAR •Physical properties are measured for the molecule as a whole •Properties are calculated using computer software •No experimental constants or measurements are involved •Properties are known as ‘Fields’ •Steric field - defines the size and shape of the molecule •Electrostatic field - defines electron rich/poor regions of molecule •Hydrophobic properties are relatively unimportant Advantages over QSAR •No reliance on experimental values •Can be applied to molecules with unusual substituents •Not restricted to molecules of the same structural class •Predictive capability 24
- 25. 3D-QSAR •Comparative molecular field analysis (CoMFA) - Tripos •Build each molecule using modelling software •Identify the active conformation for each molecule •Identify the pharmacophore Method NHCH3 OH HO HO Active conformation Build 3D model Define pharmacophore 25
- 26. 3D-QSAR •A probe atom is placed at each grid point in turn Method •Measure the steric or electrostatic interaction of the probe atom with the molecule at each grid point . . . . . Probe atom 26
- 27. 3D-QSAR •Define fields using contour maps round a representative molecule Method 27
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- 29. Properties Explored in QSAR 29
- 30. 30 Any quaries Ask me: inboxeswar@gmail.com