Structure Activity Relationships (SAR) And Quantitative Structure Activity Relationships (QSAR) Sachin Shinde S.M.Joshi College ,Hadapsar,Pune

What is SAR It is intended to give the relationship between chemical structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for biological effect How is it carried out This involves synthesis and testing of all analogues for biological activity and comparing them with the original compound. If an analogue shows a significant lower activity, then the group that has been modified must be important. If the activity remains unchanged, then the group is not essential.

Lead developement Once the structure of lead compound is known, the medicinal chemist moves on to study its SAR. The aim is to discover which parts of the molecule are important to biological activity (Pharmacophore) and which are not. SAR is synthesizing compounds, where one particular functional group of the molecule is removed or altered. In this way it is possible to find out which groups are essential and which are not for biological effect.

Identification of Pharmacophore by chopping the molecule

The binding role of double bonds

Bioisosterism for creating new analogues Bioisosteres - substituents or groups with chemical or physical similarities that produce similar biological properties. Can attenuate toxicity, modify activity of lead, and/or alter pharmacokinetics of lead.

Classical Isosteres

Non-Classical Isosteres Do not have the same number of atoms and do not fit steric and electronic rules of classical isosteres, but have similar biological activity.

Drug analogs can also be made by I) Changing the size and shape of the lead molecule - number of methylene groups in chains and rings - increasing or decreasing the degree of unsaturation introducing or removing a ring system Changing the stereochemistry II) Introduction of a new substituent

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Introduction of new substituents Methyl groups Paracetamol Reduced hepatotoxicity

Solubility and membrane permeability Adding polar groups Adding polar groups increases polarity and decreases hydrophobic character Useful for targeting drugs vs. gut infections Useful for reducing CNS side effects Antifungal agent with poor solubility - skin infections only Systemic antifungal agent improved blood solubility Disadvantage: May introduce unwanted side effects

Drug stability Metabolic blockers Rationale: Metabolism of drugs usually occur at specific sites. Introduce groups at a susceptible site to block the reaction Increases metabolic stability and drug lifetime Oral contraceptive - limited lifetime

Drug Designing using Quantitative Structure- Activity Relationships (QSAR)

What is QSAR? QSAR is a mathematical relationship between biological activity of a molecular system and its geometric and chemical characteristics. QSAR attempts to find consistent relationship between biological activity and molecular properties, so that these “rules” can be used to evaluate the activity of new compounds.

Estimation of the concentration of given solution O.D O.D Concentration mg/ml concentration y = mx+c

Introduction to QSAR 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

ADME

Intermolecular binding forces Electrostatic or ionic bond Hydrogen Bonds Binding site Hydrophobic regions Transient dipole on drug d+ d- van der Waals interaction DRUG d+ d- d- d+ Van der Waals Interactions

Structured water layer round hydrophobic regions Ion-dipole interactions d+ d- R C O d+ d- R C O Binding site Binding site Hydrophobic interactions Binding site Drug DRUG Binding Binding site Drug DRUG Hydrophobic regions Water Unstructured water Increase in entropy Structured water layer round hydrophobic regions

There are two important aspects in drug design and drug strategies to improve : Pharmacodynamics properties: to optimize the interaction of the drug with its target. Pharmacokinetics properties: to improve the drug's ability to reach its target & to have acceptable lifetime. Pharmacodynamics and pharmacokinetics should have equal priority in influencing which strategies are used and which analogues are synthesized.

New compounds with improved biological activity QSAR and Drug Design Compounds + biological activity QSAR New compounds with improved biological activity

Example of a QSAR Anti-adrenergic Activity and Physicochemical Properties of 3,4- disubstituted N,N-dimethyl-a-bromophenethylamines p = Lipophilicity parameter s+ = Hammett Sigma+ (for benzylic cations) Es(meta) = Taft’s steric parameter

Example of a QSAR... m-X p-Y p s+ Es(meta) log (1/C)obs log (1/C)a log (1/C)b H H 0.00 0.00 1.24 7.46 7.82 7.88 F H 0.13 0.35 0.78 7.52 7.45 7.43 H F 0.15 -0.07 1.24 8.16 8.09 8.17 Cl H 0.76 0.40 0.27 8.16 8.11 8.05 Cl F 0.91 0.33 0.27 8.19 8.38 8.34 Br H 0.94 0.41 0.08 8.30 8.30 8.22 I H 1.15 0.36 -0.16 8.40 8.61 8.51 Me H 0.51 -0.07 0.00 8.46 8.51 8.36 Br F 1.09 0.34 0.08 8.57 8.57 8.51 H Cl 0.70 0.11 1.24 8.68 8.46 8.60 Me F 0.66 -0.14 0.00 8.82 8.78 8.65 H Br 1.02 0.15 1.24 8.89 8.77 8.94 Cl Cl 1.46 0.51 0.27 8.89 8.75 8.77 Br Cl 1.64 0.52 0.08 8.92 8.94 8.94 Me Cl 1.21 0.04 0.00 8.96 9.15 9.08 Cl Br 1.78 0.55 0.27 9.00 9.06 9.11 Me Br 1.53 0.08 0.00 9.22 9.46 9.43 H I 1.26 0.14 1.24 9.25 9.06 9.26 H Me 0.52 -0.31 1.24 9.30 8.87 8.98 Me Me 1.03 -0.38 0.00 9.30 9.56 9.47 Br Br 1.96 0.56 0.08 9.35 9.25 9.29 Br Me 1.46 0.10 0.08 9.52 9.35 9.33 Calc. Calc.

Example of a QSAR... QSAR Equation a: (using 2 variables) log (1/C) = 1.151 p - 1.464 s + + 7.817 (n = 22; r = 0.945) QSAR Equation b: (using 3 variables) log (1/C) = 1.259 p - 1.460 s + + 0.208 Es(meta) + 7.619 (n = 22; r = 0.959)

Hydrophobicity of the Molecule Partition Coefficient P = [Drug in octanol] [Drug in water] High P High hydrophobicity

Hydrophobicity of the Molecule Example 2 General anaesthetic activity of ethers (parabolic curve - larger range of log P values) Log P o Log (1/C) Log 1 C æ è ö ø = - 0.22(logP) 2 + 1.04 logP 2.16 Optimum value of log P for anaesthetic activity = log Po log 1/C = - k1 (log P)2 + k2 log P + k3 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 concentrations.

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

Hydrophobicity of Substituents - the substituent hydrophobicity constant (p) π = log PX – log PH Benzene (Log P = 2.13) Chlorobenzene = 2.84) Benzamide = 0.64) C l O N H 2 Example : pCl = 0.71 pCONH = -1.49 2 Positive values imply substituents are more hydrophobic than H Negative values imply substituents are less hydrophobic than H

p values for various substituents on aromatic rings CH3 t-Bu OH CONH2 CF3 Cl Br F 0.52 1.68 -0.67 -1.49 1.16 0.71 0.86 0.14 Theoretical Log P for chlorobenzene = log P for benzene + p for Cl = 2.13 + 0.71 = 2.84 Theoretical Log P for meta-chlorobenzamide = log P for benzene + p for Cl + p for CONH2 = 2.13 + 0.71 - 1.49 = 1.35

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

Hammett Substituent Constant (s) X= electron withdrawing group (e.g. NO2) Charge is stabilised by X Equilibrium shifts to right KX > KH s X = log K H logK - Positive value

Hammett Substituent Constant ( s) X= electron donating group (e.g. CH3) Charge destabilised Equilibrium shifts to left KX < KH s X = log K H logK - Negative value

Hammett Substituent Constant (s) EXAMPLES: sp (NO2) = 0.78 sm (NO2) = 0.71 meta-Substitution e-withdrawing (inductive effect only) para-Substitution e-withdrawing (inductive + resonance effects)

Hammett Substituent Constant (s) EXAMPLES: sm (OH) = 0.12 sp (OH) = -0.37 meta-Substitution e-withdrawing (inductive effect only) para-Substitution e-donating by resonance more important than inductive effect

Hammett Substituent Constant (s) QSAR Equation: Log (1/C) = 2.282 s – 0.348 Diethylphenylphosphates (Insecticides) Conclusion : e-withdrawing substituents increase activity

Steric Effects Examples are: ·        Taft’s steric factor (Es) (~1956), an experimental value based on Ester hydrolysis 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

Steric Factors Taft’s Steric Factor (Es) Measured by comparing the rates of hydrolysis of substituted aliphatic esters against a standard ester under acidic conditions Es = log kx - log ko kx represents the rate of hydrolysis of a substituted ester ko represents the rate of hydrolysis of the parent ester Limited to substituents which interact sterically with the tetrahedral transition state for the reaction Cannot be used for substituents which interact with the transition state by resonance or hydrogen bonding May undervalue the steric effect of groups in an intermolecular process (i.e. a drug binding to a receptor)

Steric Factors MR = (n - 1) 2) x mol. wt. density Molar Refractivity (MR) - a measure of a substituent’s volume MR = (n 2 - 1) 2) x mol. wt. density Correction factor for polarisation (n=index of refraction) Defines volume

Steric Factors Verloop Steric Parameter - calculated by software (STERIMOL) - gives dimensions of a substituent - can be used for any substituent L B 3 4 B4 B3 B2 B1 Example - Carboxylic acid

Hansch Equation Example:Antimalarial activity of phenanthrene aminocarbinols Log 1 C æ è ö ø = - 0.015 (logP) 2 + 0.14 logP 0.27 S p X 0.40 Y 0.65 s 0.88 2.34 Conclusions: Activity increases slightly as log P (hydrophobicity) increases (note that the constant is only 0.14) Parabolic equation implies an optimum log Po value for activity Activity increases for hydrophobic substituents (esp. ring Y) Activity increases for e-withdrawing substituents (esp. ring Y)

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. Allows an easy identification of suitable substituents for a QSAR analysis which includes both relevant properties

Craig Plot Allows an easy identification of suitable substituents for a QSAR analysis which includes both relevant properties Choose a substituent from each quadrant to ensure orthogonality Choose substituents with a range of values for each property

Craig Plot Craig plot shows values for 2 different physicochemical properties for various substituents -p +p Example: -s +p +s +p -s -p +s -p

Topliss Scheme: A noncomputerised, nonmathematical & nonstatistical method Used to decide which substituents to use if optimising compounds one by one (where synthesis is complex and slow and bioassays are easy & fast) Example: Aromatic substituents +s +p -s -p +s +p -s +p -s +p -s +p

Topliss Scheme Rationale Rationale Replace H with para-Cl (+p and +s) Act. Little change Act. +p and/or +s advantageous favourable p unfavourable s +p and/or +s disadvantageous add second Cl to increase p and s further replace with Me (+p and -s) replace with OMe (-p and -s) Further changes suggested based on arguments of p, s and steric strain

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