This document provides an overview of quantitative structure-activity relationship (QSAR) modeling techniques including Hansch analysis, Free-Wilson analysis, and Topliss schemes. It discusses how QSAR relates the biological activity of drugs to their physicochemical properties through equations. Specifically, it explains that Hansch equations relate activity to hydrophobicity, electronic effects, and steric factors. Examples of Hansch equations are provided. The Free-Wilson approach derives equations based on the presence or absence of substituents. Topliss schemes provide a methodical approach to substituent selection for optimization.
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.
PHARMACOHORE MAPPING AND VIRTUAL SCRRENING FOR RESEARCH DEPARTMENTShikha Popali
THE PHARMACOPHORE MAPPING AND VIRTUAL SCRRENING , THESE PRESENTATION INCLUDES THE DEATIL ACCOUNT ON PHARMACOPHORE, MAPPING, ITS IDENTIFIATION FEATURES, ITS CONFORMATIONAL SEARCH, INSILICO DRUG DESIGN, VIRTUAL SCREENING, PHARMACOPHORE BASED SCREENING
What is QSAR?, introduction to 3D QSAR, CoMFA, CoMSIA, Case Study on CoMFA contour maps analysis and CoMSIA interactive forces between ligand and receptor, various Statistical techniques involved in QSAR
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.
PHARMACOHORE MAPPING AND VIRTUAL SCRRENING FOR RESEARCH DEPARTMENTShikha Popali
THE PHARMACOPHORE MAPPING AND VIRTUAL SCRRENING , THESE PRESENTATION INCLUDES THE DEATIL ACCOUNT ON PHARMACOPHORE, MAPPING, ITS IDENTIFIATION FEATURES, ITS CONFORMATIONAL SEARCH, INSILICO DRUG DESIGN, VIRTUAL SCREENING, PHARMACOPHORE BASED SCREENING
What is QSAR?, introduction to 3D QSAR, CoMFA, CoMSIA, Case Study on CoMFA contour maps analysis and CoMSIA interactive forces between ligand and receptor, various Statistical techniques involved in QSAR
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.
THE PRODRUG DESIGNING FOR NEW SELECTION AND FORMULATION OF DRUG COMPATIBLE WITH API I.E. ACTIVE PHARMACUTICAL INGREDIENT, AND ITS EFFECT WHICH SHOULD BE 0. THE DRUG COMBINED WITH API AND AVILABLE IN MARKET AND DRUGS NEED TO BE COMBINE ARE ALSO DISCUSSED WITH ITS STRUCTURE AND SAR, AND COVERED AS PER THE SYLLABUS OF PCI.
Pharmacophore mapping and virtual screening(CADD) ppt.pptxMZzaddy
Pharmacophore mapping is a technique used in drug discovery to identify the key chemical and structural features of a molecule that are necessary for it to interact with a biological target in a specific way. It involves the identification and mapping of specific functional groups, atom types, and other molecular properties that are required for binding to the target. Pharmacophore mapping is often used in combination with other computational techniques, such as molecular docking and molecular dynamics simulations, to identify and optimize potential drug candidates.
Virtual screening is a computational method used in drug discovery to search large chemical databases for compounds that are likely to bind to a target of interest. Virtual screening involves the use of computational models, such as pharmacophore models, molecular docking, and molecular dynamics simulations, to predict the binding affinity and selectivity of a large number of compounds against the target. By screening virtual chemical libraries, virtual screening allows the rapid identification of potential drug candidates, which can then be further tested and optimized using experimental methods. Virtual screening is an important tool in drug discovery, as it can significantly reduce the time and costs associated with traditional drug discovery methods.
THE DRUG DESIGN AND DEVELOPMENT BASED ON DRUG DISCOVERY ,HERE ITS NEED RATIONALE ARE EXPLAINED ALSO QSAR, MOLECULAR DOCKING ITS HISTORY NEED, STRUCTURE BASED DRUG DESIGN IN EASY WAY WE HAVE MENTIONED. THIS WILL MAKE READERS EASY TO COLLECT DATA AT A PLACE ALL OVER THIS IS FOR PHARMA STUDENTS, ACADEMICS, PROFESSIONL AND OST USEFUL FOR RESEARCHERS.
THANK YOU
HOPE YOU WILL LIKE AND SHARE
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.
THE PRODRUG DESIGNING FOR NEW SELECTION AND FORMULATION OF DRUG COMPATIBLE WITH API I.E. ACTIVE PHARMACUTICAL INGREDIENT, AND ITS EFFECT WHICH SHOULD BE 0. THE DRUG COMBINED WITH API AND AVILABLE IN MARKET AND DRUGS NEED TO BE COMBINE ARE ALSO DISCUSSED WITH ITS STRUCTURE AND SAR, AND COVERED AS PER THE SYLLABUS OF PCI.
Pharmacophore mapping and virtual screening(CADD) ppt.pptxMZzaddy
Pharmacophore mapping is a technique used in drug discovery to identify the key chemical and structural features of a molecule that are necessary for it to interact with a biological target in a specific way. It involves the identification and mapping of specific functional groups, atom types, and other molecular properties that are required for binding to the target. Pharmacophore mapping is often used in combination with other computational techniques, such as molecular docking and molecular dynamics simulations, to identify and optimize potential drug candidates.
Virtual screening is a computational method used in drug discovery to search large chemical databases for compounds that are likely to bind to a target of interest. Virtual screening involves the use of computational models, such as pharmacophore models, molecular docking, and molecular dynamics simulations, to predict the binding affinity and selectivity of a large number of compounds against the target. By screening virtual chemical libraries, virtual screening allows the rapid identification of potential drug candidates, which can then be further tested and optimized using experimental methods. Virtual screening is an important tool in drug discovery, as it can significantly reduce the time and costs associated with traditional drug discovery methods.
THE DRUG DESIGN AND DEVELOPMENT BASED ON DRUG DISCOVERY ,HERE ITS NEED RATIONALE ARE EXPLAINED ALSO QSAR, MOLECULAR DOCKING ITS HISTORY NEED, STRUCTURE BASED DRUG DESIGN IN EASY WAY WE HAVE MENTIONED. THIS WILL MAKE READERS EASY TO COLLECT DATA AT A PLACE ALL OVER THIS IS FOR PHARMA STUDENTS, ACADEMICS, PROFESSIONL AND OST USEFUL FOR RESEARCHERS.
THANK YOU
HOPE YOU WILL LIKE AND SHARE
A quantitative structure-activity relationship
(QSAR) correlates measurable or calculable
physical or molecular properties to some
specific biological activity in terms of an
equation.
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
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.
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
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What is the purpose of the Sabbath Law in the Torah. It is interesting to compare how the context of the law shifts from Exodus to Deuteronomy. Who gets to rest, and why?
We all have good and bad thoughts from time to time and situation to situation. We are bombarded daily with spiraling thoughts(both negative and positive) creating all-consuming feel , making us difficult to manage with associated suffering. Good thoughts are like our Mob Signal (Positive thought) amidst noise(negative thought) in the atmosphere. Negative thoughts like noise outweigh positive thoughts. These thoughts often create unwanted confusion, trouble, stress and frustration in our mind as well as chaos in our physical world. Negative thoughts are also known as “distorted thinking”.
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3. QSAR approach attempts to identify and
quantify the physicochemical properties of a drug
and to see whether any of these properties has an
effect on the drug’s biological activity .
Introduction
4. QSAR – Physicochemical properties
• Hydrophobicity of the molecule. (log P).
• Hydrophobicity of the substituent.(the substituent hydrophobicity
constant (p) )
• Electronic properties of the substituents. (Hammett
Substituent Constant (s) )
• Steric properties of the substituents. Taft’s Steric Factor (Es)
5. The biological activity of most drugs is related to a
combination of physico-chemical properties.
In such cases, simple equations involving only one
parameter are relevant only if the other parameters are
kept constant.
In reality, this is not easy to achieve and equations which
relate biological activity to more than one parameter are
more common.
These equations are known as Hansch equations and they
usually relate biological activity to the most commonly
used physicochemical properties (logP ,electronic,and a
steric factor).
6. If the range of hydrophobicity values is limited to a small
range then the equation will be linear .
log(1/C)= k1 log P + k2s + k3 Es +k4.
If the P values are spread over a large range then the
equation will be parabolic for the same reasons.
log (1/C) = - k1(log P)2 + k2 log P + k3 s + k4 Es +k5
7. Hansch Equation
•A QSAR equation relating various physicochemical properties to
the biological activity of a series of compounds
•Usually includes log P, electronic and steric factors
•Start with simple equations and elaborate as more structures are
synthesised
•Typical equation for a wide range of log P is parabolic
Log 1
C
= -k (logP)2+ k2 logP+ k3s + k4 Es + k51
8. Hansch Equation
Log
1
C
= 1.22p - 1.59s + 7.89
Conclusions:
•Activity increases if p is +ve (i.e. hydrophobic substituents)
•Activity increases if s is negative (i.e. e-donating substituents)
Example: Adrenergic blocking activity of b-halo-b-arylamines
CH CH2 NRR'
XY
9. 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)
Hansch Equation
Example : Antimalarial activity of phenanthrene aminocarbinols
X
Y
(HO)HC
CH2NHR'R"
Log
1
C
= -0.015 (logP)
2
+ 0.14 logP + 0.27 S p
X
+ 0.40 Sp
Y
+ 0.65 Ss
X
+ 0.88 Ss
Y
+ 2.34
10. Substituents must be chosen to satisfy the following criteria;
• A range of values for each physicochemical property studied.
• Values must not be correlated for different properties (i.e. they
must be orthogonal in value)
• At least 5 structures are required for each parameter studied
Substituent H Me Et n-Pr
p 0.00 0.56 1.02 1.50
MR 0.10 0.56 1.03 1.55
11. Craig Plot
Craig plot shows values for 2 different physicochemical properties for various
substituents
Example:
.
+
-
-.25
.75
.50
1.0
-1.0
-.75
-.50
.25
-.4-.8-1.2-1.6-2.0 2.01.61.2.8.4.
. . .
.
.
.
.
.. . .
.
.
.
.
.
.....
CF3SO2
CF3
Me
Cl Br I
OCF3
F
NMe2
OCH3
OH
NH2
CH3CONH
CO2H
CH3CO
CN
NO2
CH3SO2
CONH2
SO2NH2
Et
t-Butyl
SF5
-p +p
-s +p
+s +p
-s -p
+s -p Electron withdrawing
hydrophillic
Electron donating
hydrophillic
Electron
withdrawing
hydrophobic
Electron donating
hydrophobic
12. Topliss Scheme
Used to decide which substituents to use if optimising compounds one by one (where
synthesis is complex and slow)
Example: Aromatic substituents
L E M
ML EL E M
L E M
L E M
See Central
Branch
L E M
H
4-Cl
4-CH34-OMe 3,4-Cl2
4-But
3-CF3-4-Cl
3-Cl 3-Cl 4-CF3
2,4-Cl2
4-NO2
3-NMe2
3-CF3-4-NO2
3-CH3
2-Cl
4-NO2
3-CF3
3,5-Cl2
3-NO2
4-F
4-NMe2
3-Me-4-NMe2
4-NH2
13. Rationale
Replace H with
para-Cl (+p and +s)
+p and/or +s
advantageous
Favourable p
unfavourable s
+p and/or +s
disadvantageous
ACT.
Little
change
ACT .
Further changes suggested based on arguments of p, s and
steric strain
Topliss Scheme
Replace with Me
(+p and -s)
Add second Cl
to increase p
and s further
Replace with OMe
(-p and -s)
14. Free-Wilson Approach
•The biological activity of the parent structure is measured and compared
with the activity of analogues bearing different substituents
•An equation is derived relating biological activity to the presence or absence
of particular substituents
Activity = k1X1 + k2X2 +.…knXn + Z
•Xn is an indicator variable which is given the value 0 or 1 depending on whether the
substituent (n) is present or not
•The contribution of each substituent (n) to activity is determined by the value of kn
•Z is a constant representing the overall activity of the structures studied
Method
15. Free-Wilson Approach
•No need for physicochemical constants or tables
•Useful for structures with unusual substituents
•Useful for quantifying the biological effects of molecular features that cannot be
quantified or tabulated by the Hansch method
Advantages
Disadvantages
•A large number of analogues need to be synthesised to represent each different
substituent and each different position of a substituent
•It is difficult to rationalise why specific substituents are good or bad for activity
•The effects of different substituents may not be additive
(e.g. intramolecular interactions)
16. Patrick L . Graham “ An introduction to medicinal
chemistry ’’ 4th edition by Oxford University, NewYork.
• http://www.ccl.net/qsar/archives/0207/0029.html
• http://www.srmuniv.ac.in/downloads/qsar.pdf&sa=
