History and development of QSAR: Physicochemical parameters presented by Dhanashree Kavhale M.Pharm.(pharmaceutical Chemistry) II sem.

1. History and development of QSAR :
Physicochemical Parameters
Presented by
Dhanashree R. Kavhale
M. Pharm. (Pharmaceutical Chemistry) Sem- II
Department of Pharmaceutical Sciences
Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur - 440033

2. Contents
1. Introduction
2. SAR v/s QSAR
3. History of QSAR
4. Development of QSAR
5. QSAR and drug design
6. Physicochemical parameters
7. References
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3. What is QSAR….?
Measurable molecular properties Some biological activities
In form of equation
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4. Continue..
 Quantifying the relationship between physicochemical properties and
biological activity.
 mathematical relationship which correlates measurable or calculable molecular
properties to some specific biological activity in terms of an equation.
 so that it can be used to evaluate the activity of new compounds.
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5. Continue..
• QSAR derived equation take the general form:
• Biological activity = function(parameters)
• Activity is expressed as log(1/c).
• Where, c is the minimum concentration required to cause a defined biological
response.
Purpose of QSAR:
 To predict biological activity and physic-chemical properties by rational means.
 To comprehend and rationalize the mechanisms of action within a series of
chemicals.
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6. SAR v/s QSAR
SAR
• Used to develop a new drug that has increased
activity.
• Mainly done by lead molecule.
• It doesn't consider the change in potency.
QSAR
• Mainly help in drug designing purpose.
• Optimize the properties of lead compound.
• Deals with the potency and change in efficacy.
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7. History of QSAR
• 1900 : H. H. Meyer and C. E. Overton : Lipoid theory of narcosis
• 1930 : L. Hammett: Electronic sigma constants
• 1964 : C. Hansch and T. Fujita: QSAR
• 1984 : P. Andrews: Affinity contributions of functional groups
• 1985 : P. Goodford: GRID (hot spots at protein surface)
• 1988 : R. Cramer: 3D QSAR
• 1992 : H. J. Böhm: LUDI interaction sites, docking, scoring
• 1997 : C. Lipinski: Bioavailability rule of five
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8. Development of QSAR
 QSAR modeling was founded by Corwin Hansch.
 Tools for modeling of physical and biological properties of chemicals.
 QSAR models find broad applications for assessing the potential impacts of
chemicals, nanomaterials on human health and ecological systems.
 Achieved by developing QSAR models and employed them for virtual screening
followed by experimental validation.
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9. Steps in development of QSAR
Data
understanding
Molecular
descriptors
Data processing
Data cleaning
Data
transformation
Multivariate
analysis
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10. Physicochemical Parameters
Electronic parameters
 Electron distribution in the drug molecules affect the drug distribution and activity.
 Non polar and polar drugs are readily transported through the membrane in
unionised form than ionised form.
 When drug reaches to the target site its electron distribution and structure, controls
the type of bond it will form with the target molecules.
 The bond formations influences the drug biological activity.
 Two type of electronic parameters are as follows:
1. Hammett equation
2. Dipole movement
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11. Linear Free Energy Relationships
 Linear Free Energy Relationships allow a correlation of substituents with a
reaction rate, biological activity, pKa, etc.
 To help us understand the magnitude of the sensitivity of parameter to changing
substituents, with respect to a reference reaction.
 What Hammett accomplished :
 the Hammett equation describes a linear free energy relationship
relating reaction rate and equilibrium constant for many reactions
involving benzoic acid derivatives.
 To relate the biological activity of a series of compounds to their physicochemical
parameters in a quantitative fashion using a mathematical formula.
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12. Hammett equation
 It is the measure of substituents ability to donate or withdraw the electron.
 Determined by using the dissociations of series of benzoic acid substituted
derivatives in relation to pure benzoic acid
 Hammett substitution(𝜎) constant of the particular substituent(x) is defined
by using formula.
 𝜎𝑥 = log(
𝑘𝑅
𝑘𝐻
)
 Where, 𝑘𝑅 = dissociation constant of substituted acid
𝑘𝐻 = dissociation constant of unsubstituted acid
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13. Continue..
 𝜎 value depends upon inductive and resonance effect.
 And also depends upon whether the substituent is meta or para.
 Benzoic acid having EWG have larger 𝒌𝑹 value than benzoic acid. So 𝜎 value
is positive.
 Benzoic acid having EDG have smaller 𝒌𝑹 value than benzoic acid. So 𝜎 value
is negative.
 Limitation:
 It doesn't hold for ortho substituents, this characteristic is known as ortho effect.
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14. QSAR and Drug Design
 To modify the chemical structure of the lead compound.
 To retain or to reinforce the desirable pharmacologic effect.
 Minimizing unwanted pharmacological and physical and chemical properties.
 To use target analogs as pharmacological probes to gain better insight into the
pharmacology of the lead molecule.
 To reveal new knowledge of basic biology.
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15. References
1. Myint KZ, Xie XQ. Recent advances in fragment-based QSAR and multi-
dimensional QSAR methods. Int J Mol Sci. 2010;11(10):3846-3866.
Published 2010 Oct 8. doi:10.3390/ijms11103846.
2. Esposito EX, Hopfinger AJ, Madura JD. Methods for applying the
quantitative structure-activity relationship paradigm. Methods Mol Biol.
2004;275:131-214. doi:10.1385/1-59259-802-1:131.
3. Verma J, Khedkar VM, Coutinho EC. 3D-QSAR in drug design--a
review. Curr Top Med Chem. 2010;10(1):95-115.
doi:10.2174/156802610790232260.
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16. Thank you…
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