QSAR Method: What does QSAR Stand for in Drug Design?

Questions and Answers

What is the main purpose of Quantitative Structure-Activity Relationships (QSAR) in drug design?

To form a quantitative relationship between the biological effect and the chemistry of each chemical

When are Quantitative Structure-Activity Relationships (QSAR) used in drug design?

When there is little or no receptor information available

How are Quantitative Structure-Activity Relationships (QSAR) explained?

By correlating measurable or calculable physical or molecular properties to specific biological activity in terms of an equation

What does QSAR allow researchers to predict?

The biological activity of related drug candidates before expensive and time-consuming biological testing Signup and view all the answers

Which type of compounds are suitable for Quantitative Structure-Activity Relationships (QSAR)?

A range of structurally similar compounds Signup and view all the answers

When was the concept of Quantitative Structure-Activity Relationships (QSAR) introduced?

1964 Signup and view all the answers

What did Crum-Brown and Fraser express in 1868?

The idea that the physiological action of a substance is a function of its chemical composition and constitution Signup and view all the answers

What does QSAR stand for?

Quantitative Structure-Activity Relationship Signup and view all the answers

What must the compounds studied in QSAR be?

Structurally related, act at same targets, and have the same mechanism of action Signup and view all the answers

What do descriptors of a compound contribute to in QSAR?

They contribute to a linearly additive way to its biological activity Signup and view all the answers

Which equation describes the linear correlation between Lipophilicity (log P) and biological activity?

Biological Activity = f (log P) Signup and view all the answers

In the context of QSAR, what do chemoinformatics methods do?

Extract descriptors from molecular structure and define a mapping correlating them with the activity in question Signup and view all the answers

What is the purpose of the Hammett constant (σ) in drug design?

To predict the effect of substitution on the acid dissociation constants of substituted benzoic acids Signup and view all the answers

What does a positive value of Hammett constant (σ) indicate about substituents?

They are electron-withdrawing groups, such as Cl and NO2, due to increased ionization Signup and view all the answers

What is the purpose of the hydrophobicity constant (π) in drug design?

To measure the relative hydrophobicity of a substituent Signup and view all the answers

What do negative values of Hammett constant (σ) indicate about substituents?

They are electron-donating groups, such as OH and NH2, due to decreased ionization Signup and view all the answers

What is the significance of the partition coefficients in drug design?

To study how a molecule distributes between two immiscible solvents Signup and view all the answers

How is the hydrophobicity constant (π) determined?

By using the octanol/water system to measure a series of partition coefficients Signup and view all the answers

Which parameter indicates more hydrophilic substituents?

Negative π Signup and view all the answers

What is the typical Es value for the substituent t-Bu?

-2.78 Signup and view all the answers

According to the Hansch equation, which parameter is most important for biological activity?

Es Signup and view all the answers

In the parabolic Hansch equation, why was the quadratic π2 term introduced to the model?

To deal with extended hydrophobicity ranges Signup and view all the answers

What does a negative σ value in the Hansch equation indicate for biological activity?

Increases biological activity Signup and view all the answers

In the context of SAR, if a penicillin derivative requires a Lipophilic and bulky R group to increase activity, which equation best describes this relationship?

$log(1/C) = 0.21 \sigma - 0.48 \pi + 0.57 Es + 0.02$ Signup and view all the answers

Which substituent has an Es value indicating little steric resistance to hydrolysis?

$Me$ Signup and view all the answers

What does a positive π value indicate?

More lipophilic substituents Signup and view all the answers

What do typical Es values represent?

$Steric$ effects Signup and view all the answers

'Log Biological Activity = a log p + b σ + c Es' is an equation associated with which concept?

$Hansch equation$ Signup and view all the answers

Study Notes

Quantitative Structure-Activity Relationships (QSAR) in Drug Design

QSAR is a computational method used to predict the biological activity of compounds based on their chemical structure and physicochemical properties.
QSAR is used to design and optimize drug molecules by identifying the most promising compounds with desired biological activity.
QSAR explains the relationship between the chemical structure of a compound and its biological activity.

History of QSAR

The concept of QSAR was introduced in 1868 by Crum-Brown and Fraser, who expressed the idea that the physiological action of a compound is a function of its chemical structure.

QSAR Requirements

QSAR analysis requires a set of compounds with similar structures and known biological activity.
Compounds studied in QSAR must have similar chemical structures and varying substituents.

Descriptors in QSAR

Descriptors of a compound contribute to the development of QSAR models by providing quantitative measures of its physicochemical properties.
Descriptors include lipophilicity (log P), electronic effects (σ), and steric effects (Es).

Hammett Constant (σ)

The Hammett constant (σ) is a measure of the electronic effect of a substituent on the biological activity of a compound.
A positive value of Hammett constant (σ) indicates that the substituent is electron-withdrawing.
A negative value of Hammett constant (σ) indicates that the substituent is electron-donating.

Hydrophobicity Constant (π)

The hydrophobicity constant (π) is a measure of the lipophilicity of a compound.
The hydrophobicity constant (π) is determined experimentally using the partition coefficient (log P).
A positive value of π indicates that the substituent is lipophilic (hydrophobic).
A negative value of π indicates that the substituent is hydrophilic.

Hansch Equation

The Hansch equation is a QSAR model that describes the linear correlation between lipophilicity (log P) and biological activity.
The Hansch equation is: log Biological Activity = a log P + b σ + c Es.
In the Hansch equation, the parameter π is most important for biological activity.
The quadratic π2 term was introduced to the Hansch equation to describe the parabolic relationship between lipophilicity and biological activity.
A negative σ value in the Hansch equation indicates that the substituent has an unfavorable electronic effect on biological activity.

Steric Effects (Es)

The steric effect (Es) is a measure of the steric resistance of a substituent to hydrolysis.
Typical Es values represent steric effects, with higher values indicating more steric resistance.
The substituent t-Bu has an Es value indicating little steric resistance to hydrolysis.

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Quantitative Structure Activity Relationships (QSAR) in Drug Design