This document discusses quantitative structure-activity relationship (QSAR) parameters that are used to develop mathematical models relating a compound's molecular properties to its biological activity. It describes three main types of QSAR parameters: lipophilic parameters like partition coefficient and molar refractivity, electronic parameters like the Hammett constant, and steric parameters such as Taft's steric factor and Verloop steric parameter. Lipophilicity parameters measure a compound's affinity for lipid versus aqueous phases, while electronic and steric parameters account for effects of substituents on properties like ionization, polarity, and molecular bulkiness that influence biological interactions. Developing relationships between activity and these physicochemical parameters allows evaluation and design of new drug candidates.
Quantitative structure - activity relationship (QSAR)
Why QSAR?
costs – 800M$ to bring a new drug to market
Patent life time is limited (generic drugs)
Synthesis / Purification of compounds is expensive and time consume-able
It is like find a needle in the haystack
QSAR helps for focusing most promising drug candidates
QSAR is a mathematical relationship between a “biological activity of a molecular system” and its “geometric and chemical characteristics”.
Such relationships holds – Equations can be drawn up- some confidence
to which should be Fit to the target
QSAR what actually do?
IDENTIFY AND QUANTIFY the Physico-chemical properties effect on Drug’s Biological activity
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
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
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
No reliance on experimental values
Can be applied to molecules with unusual substituents
Not restricted to molecules of the same structural class
Predictive capability
Comparative molecular field analysis (CoMFA) - Tripos
Build each molecule using modelling software
Identify the active conformation for each molecule
Identify the pharmacophore
THANKING YOU
Quantitative structure - activity relationship (QSAR)
Why QSAR?
costs – 800M$ to bring a new drug to market
Patent life time is limited (generic drugs)
Synthesis / Purification of compounds is expensive and time consume-able
It is like find a needle in the haystack
QSAR helps for focusing most promising drug candidates
QSAR is a mathematical relationship between a “biological activity of a molecular system” and its “geometric and chemical characteristics”.
Such relationships holds – Equations can be drawn up- some confidence
to which should be Fit to the target
QSAR what actually do?
IDENTIFY AND QUANTIFY the Physico-chemical properties effect on Drug’s Biological activity
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
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
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
No reliance on experimental values
Can be applied to molecules with unusual substituents
Not restricted to molecules of the same structural class
Predictive capability
Comparative molecular field analysis (CoMFA) - Tripos
Build each molecule using modelling software
Identify the active conformation for each molecule
Identify the pharmacophore
THANKING YOU
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
SAR versus QSAR, History and development of QSAR, Types of physicochemical
parameters, experimental and theoretical approaches for the determination of
physicochemical parameters such as Partition coefficient, Hammet’s substituent
constant and Taft’s steric constant. Hansch analysis, Free Wilson analysis, 3D-QSAR
approaches like COMFA and COMSIA.
In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
This is a PRESENTATION just to help students to easily understand one of the method of drug designing i.e. QSAR.. this is a combination of many slides and books..this is not my personal.
Drug excipient incompatibilities are major concerns in formulation development.
Selection of the proper excipient during preformulation studies is of prime importance.
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1. QSAR PARAMETERS
Dept. of Medicinal Chemistry,
SREE DATTHA INSTITUTE OF PHARMACY,
Sheriguda, Ibrahimpatnam, Hyderabad, 501510.
Presented by:
Ashish dalpati (16U21R0051)
Under the guidance of:
Ms. G. Nikitha (M. pharm)
SREE DATTHA INSTITUTE OF PHARMACY 1
3. INTRODUCTION
• QSAR(Quantitative Structure Activity Relationship), proposed by “Corwen
Hansch” is a mathematical relationship between a 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.
• QSAR involves the derivation of mathematical formula which relates the biological
activities of agroup of compounds to their measurable physicochemical parameters. These
parameters have major influence on the drug’s activity. QSAR derived equation take the
generalform:
• Biologicalactivity =function(parameters)
• Activity isexpressedaslog(1/c).Cisthe minimum concentration required to causea
defined biologicalresponse SREE DATTHA INSTITUTE OF PHARMACY 3
4. QSAR PARAMETERS
Various parameters used in QSAR studies are:
Lipophilic Parameters: partition coefficient,
molar refractivity
Electronic Parameters: Hammet constant
Steric Parameters: Taft’s constant, verloop
steric parameter
SREE DATTHA INSTITUTE OF PHARMACY 4
5. LIPOPHILIC PARAMETERS
• Lipophilic character of a drug is
crucial to know how easily it
crosses the cell membrane and is
also important in drug-receptor
interactions.
• Lipophilicity of a drug is measured
experimentally by testing the drugs
relative distribution which is
known as partition coefficient.
1. Partition coefficient:
• Partition coefficient P usually
expressed as logP.
• It is defined as p=
𝑥 𝑜𝑐𝑡𝑎𝑛𝑜𝑙
𝑥 𝑎𝑞𝑢𝑒𝑜𝑢𝑠
• P is a measure of the relative
affinity of a molecule for the lipid
and aqueous phase in the absence
of ionization.
• 1-Octanol is a most frequently used
lipid phase in pharmaceutical
research.
• LogP for a molecule can be
calculated from a sum of
fragmental or atom based terms
plus various corrections.
• LogP = Σ fragments + Σ corrections
SREE DATTHA INSTITUTE OF PHARMACY 5
7. 2. Molar Refractivity:
• Molar refractivity is a term which determines the size and
polarizability of molecules as it is closely related with molar
properties and refractive index of particular substance which is being
tested.
• Molar refractivity is a measure of molar volume corrected by
refractive index independent of physical factors and is useful in
differentiating the structurally different compounds.
SREE DATTHA INSTITUTE OF PHARMACY 7
8. ELECTRONIC PARAMETERS
• The electronic effect of various substituent will clearly have an effect
on drug ionization and polarity.
• Have an effect on how easily drug can pass through the cell
membrane or how strongly it can interact with a binding site.
SREE DATTHA INSTITUTE OF PHARMACY 8
9. The Hammett Constant (σ):
• σ= log (Kx/Ko)
• σ=Hammet constant
• Kx=benzoic acid substituted by the group x
• Ko=dissociation constant of benzoic acid
• Hammett constant takes into account both resonance and inductive
effects; thus, the σ value depends on para or meta position of the
substituent.
• -ortho substituents are not measured due to steric effects.
SREE DATTHA INSTITUTE OF PHARMACY 9
11. STERIC PARAMETERS
• It is a measure of the bulkiness of the group it represents and it
effects on the closeness of contact between the drug and receptor
site
• Bulky substituent may help to orient a drug property for maximum
binding and increase activity.
SREE DATTHA INSTITUTE OF PHARMACY 11
12. 1. Taft’s steric factor/constant (Es):
• It is measured by the comparing the rate of hydrolysis of substituted
aliphatic esters against a standard ester under acidic condition
SREE DATTHA INSTITUTE OF PHARMACY 12
/
13. 2. Verloop Steric Parameter:
• Calculated by software STERIMOL
• Gives dimensions of substituent from the standard bond angle,
vander waals radii, bond length.
SREE DATTHA INSTITUTE OF PHARMACY 13