(PT-613) Medchem

Name of the Topic: QSAR (Quantitative Structure Activity Relationship)
Examination: 1st Continuous Assessment (1st CA)

Name: Suvojit Basak
Roll Number: 35601921045
Registration Number: 213560201910045
Semester: 6th
Year: 3rd
Subject: Medicinal Chemistry III
Paper Code: PT 613
Academic Session: 2023-2024
Global College of Pharmaceutical Technology

(A Unit of National Centre for Development of Technical Education)
QSAR (Quantitative Structure Activity Relationship)
Introduction:
• QSAR is a method developed by “Corwen Hansch” in early 1960s.
• It is used to quantify the relationship between the chemical structure of a drug and its biological activity. QSAR = chemical
structure of a Drug x biological activity.
• This method increases the probability of finding active compounds among the eventually synthesized ones, thus keeping
synthetic & screening efforts within reasonable limits in relation to the success rate.
• QSAR transforms the chemical structures of a drug or compound ,to set a numerical parameters or descriptors. Various
parameters are
• Physicochemical parameters- solubility, log P ,protein binding, partition coefficient etc.
• The physicochemical properties are relevant to the biological activity.
• QSAR also applies mathematically derived formulas which correlate the physicochemical parameters and the biological
activity of a drug or compound.
QSAR = f(physicochemical properties) x (biological activity)
• • QSAR was further assisted by “Louis Hammett”.
• He gave correlation between the electronic properties of organic compound ‘a’ & ‘b’ with its reactivity and equilibrium
constant.
Biological activity = f(C) C = Physicochemical properties and structural descriptors of a drug
• QSAR is not the final answer to drug discovery but one of the refined tool for drug development.
Definition:
Quantitative Structure-Activity Relationship (QSAR) is a computational modeling technique used in drug discovery
and chemical modeling. It involves the quantitative analysis of the relationship between the chemical structure of a
compound and its biological activity or other properties.
Applications of QSAR:
1. Drug Discovery: QSAR is widely used in drug discovery to predict the activity, toxicity, and other properties of
new compounds. This helps in the identification of potential drug candidates and optimization of their properties.
2. Environmental Modeling: QSAR is also used in environmental modeling to predict the toxicity and
environmental fate of chemicals. This helps in the assessment of the potential risks associated with the use of
chemicals.
3. Material Design: QSAR can be applied to the design of new materials with desired properties. By understanding
the relationship between the structure and properties of materials, researchers can design materials with specific
characteristics.
4. Toxicology: QSAR is used in toxicology to predict the toxicity of compounds based on their chemical structure.
This helps in the assessment of the potential risks associated with exposure to chemicals.
Limitations of QSAR:
• It fails to interpret drug-receptor interaction in biochemical terms.
• It fails to quantitatively described effects of substituents on non-covalent intramolecular interactions.
Physiochemical parameters used in QSAR:
Various parameters which are use in QSAR studies are-
1. Lipophilic parameters: partition coefficient, n- substitution constant
2. Electrophilic parameters: Hammet’s constant, dipole moment
3. Steric parameters: Taft’s constant, molar refractivity, Verloop steric parameter.
 Partition coefficient:
• a pharmaceutical sciences, partition coefficient is the ration of concentration of a compound in the two phases of a
mixture of two immisible liquids at equilibrium.
• The Partition coefficient is a ratio of concentrations of unionized drug or compound between the two liquid phases.
• The logarithm of the ratio of concentrations of the unionized solute in the solvents is called log P.
• One of the solvent is water and the other one is non polar solvent.
• Log P value is also known as a measure of lipophilicity.
• For example - in octanol-water system is
log P oct/wat = log [solute] unionized octanol/ [solute] unionized water
log P = log [organic phase]/ log [aqueous phase] (Unionized compound)
log P = log octanol/ water
• Log P is the ideal formula which gives reproducible values on drug absorption.
• If log P value is 0 to 1 shows good biological activity.
• -ve value or 1.2 ,1.5 = no biological activity.
• It is a dimensionless parameter.
• Higher the p value means ,more the lipophilicity ,more absorption, more pharmacological activity of the drug.
Log p =lipophilicity+ absorption = pharmacological activity of drug.
• P value varies with the type of solvent.
• Log P values are reliable index of solubility ,therapeutic activity.
 Hammet’s electronic parameter:

• Distribution of electrons in a drug molecule considerably influences the pharmacokinetic(ADME) &
pharmacodynamic activity of the drug.
• The unionized form of polar &non-polar drugs are transported across the lipoidal membrane against their ionized
counter parts.
• When drug reaches to the target site ,the distributed electrons controls the type of the bond. This bond will form
with the target site.
• The bond between target site and the drug molecule shows drug-receptor interaction and its biological activity.
• • Hammett substitution constant is a measure of Electron withdrawing group or electron donating group ability of
a drug molecule or its substituent.
• σ value is determined by comparing the dissociation constant of substituted drug with that of unsubstituted drug.
• When electron withdrawing group is attached to the benzoic acid aromatic ring .It will increase the acidic strength
of –COOH.
• +ve σ value = substituent is Electron withdrawing group.
• -ve σ value = substituent is Electron donating group.
• Therefore σ value for hydrogen is zero.
σ = Equilibrium constant for compound/ Equilibrium constant for monosubstituted compound.
• Hammett constant takes into account both resonance & inductive effect.
• σ value depends on meta or para position.
• Hammett constant gives idea about polarizing capacity, ionization, dipole moment, field effect, energy of molecular
orbit, atomic net energy etc..,
 Taft’s steric parameter:
• Taft steric parameter(Es) was the first parameter used to demonstrate the relationship between the shape & size
(bulk) of a drug, the dimensions of it’s target site, and it’s activity.
• It was followed by Charton steric parameter (v), Verloop steric parameters, molar refractivity (MR) etc.
• Taft used the relative rate constants of the acid- catalyzed hydrolysis of a- substituted methyl ethanoates to define
the steric parameter because it had been shown that these hydrolysis rates were dependent on steric factors. Taft
used methyl ethanoate as the standard and defined Es as:
• Es = log K(XCH2COOCH3) / K(CH3COOCH3)
• = log K(XCH2COOCH3) – log K (CH3COOCH3)
• Where, K= rate constsant of the appropriate hydrolysis, Value of Es = 0 when, X= CH 3

• The Es values obtained for a group using the hydrolysis data are assumed to be applicable to other structures
containing that group.
• Taft’s steric parameters:
Substituent Steric Parameter Substituent Steric Parameter
Methyl (CH3) 0.00 Phenyl (C6H5) -0.41
Ethyl (C2H5) -0.08 Fluorene (F) 0.78
Isopropyl (CH(CH3)2) -0.47 Hydrogen (H) 1.24
• The methyl based Es value can be converted into H based values by adding -1.24 to the corresponding methyl
based value.
 Hansch analysis:
• Generation of a lead model is a platform used to perform the regression analysis.
• The most frequently used model is ‘HANSCH’ model .
• Hansch model is also called as “LINEAR FREE ENERGY REACTION” model.
log (1/c) = a log p + b
C = molar concentration of the product
a & b = constant values
• Alternative model for analysis is “Free Wilson Approach” model.
• The above two methods are used to establish the productiveness of the drug molecule.
Example: Triazines (6 membered ring containing 3 Nitrogen atoms)
1. Research is going on triazines for anti-cancer activity.
2. Formula log(1/c) = a log p +b
3. If σ value is decreasing and P value is increasing – Lipophilicity and toxicity increases.
4. If σ value is increasing and P value is decreasing –Lipophilicity and toxicity decreases.
5.Biological activity is normally expressed in log value and is obtained from invitro experiment using software.
6.Determine the LD₅₀ and ED₅₀.
Conclusion:
• QSAR (Quantitative Structure-Activity Relationship) is a valuable tool in understanding the relationship between
chemical structures and biological activities.
• QSAR helps in predicting and optimizing the properties and activities of chemical compounds, saving time and
resources in drug discovery and development.

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Name of the Topic: QSAR (Quantitative Structure Activity Relationship)

Examination: 1st Continuous Assessment (1st CA)

Global College of Pharmaceutical Technology

• Physicochemical parameters- solubility, log P ,protein binding, partition coefficient etc.

• The physicochemical properties are relevant to the biological activity.

QSAR = f(physicochemical properties) x (biological activity)

• • QSAR was further assisted by “Louis Hammett”.

Biological activity = f(C) C = Physicochemical properties and structural descriptors of a drug

 Hammet’s electronic parameter:

• Where, K= rate constsant of the appropriate hydrolysis, Value of Es = 0 when, X= CH 3

Methyl (CH3) 0.00 Phenyl (C6H5) -0.41

Ethyl (C2H5) -0.08 Fluorene (F) 0.78

Isopropyl (CH(CH3)2) -0.47 Hydrogen (H) 1.24

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