Podcast
Questions and Answers
Which of the following is an example of a non-classical bioisostere?
Which of the following is an example of a non-classical bioisostere?
What is the effect of adding a bulky t-Bu group to a drug molecule?
What is the effect of adding a bulky t-Bu group to a drug molecule?
What is the result of replacing a carboxylate group with an amino group in Carbachol?
What is the result of replacing a carboxylate group with an amino group in Carbachol?
What is the purpose of bioisosteric replacement in drug design?
What is the purpose of bioisosteric replacement in drug design?
Signup and view all the answers
What is the effect of adding a polar functional group to a drug molecule?
What is the effect of adding a polar functional group to a drug molecule?
Signup and view all the answers
Which of the following is an example of an isostere?
Which of the following is an example of an isostere?
Signup and view all the answers
What is the primary goal of optimizing hydrophilic/hydrophobic properties of a drug?
What is the primary goal of optimizing hydrophilic/hydrophobic properties of a drug?
Signup and view all the answers
Which of the following is an example of masking a polar functional group to decrease polarity?
Which of the following is an example of masking a polar functional group to decrease polarity?
Signup and view all the answers
What is the purpose of adding a bulky alkyl group to a drug?
What is the purpose of adding a bulky alkyl group to a drug?
Signup and view all the answers
What is the effect of adding a polar functional group to a hydrophobic drug?
What is the effect of adding a polar functional group to a hydrophobic drug?
Signup and view all the answers
What is the purpose of the Lipinski rule of five?
What is the purpose of the Lipinski rule of five?
Signup and view all the answers
What is the result of introducing a polar hydroxyl group and more polar heterocyclic rings to a drug?
What is the result of introducing a polar hydroxyl group and more polar heterocyclic rings to a drug?
Signup and view all the answers
What is the main reason for simplifying the structure of a lead compound?
What is the main reason for simplifying the structure of a lead compound?
Signup and view all the answers
Which of the following is an advantage of rigidification?
Which of the following is an advantage of rigidification?
Signup and view all the answers
What is bioisosterism?
What is bioisosterism?
Signup and view all the answers
What is the purpose of steric shields?
What is the purpose of steric shields?
Signup and view all the answers
What is the result of adding a polar functional group to a molecule?
What is the result of adding a polar functional group to a molecule?
Signup and view all the answers
What is the goal of lead optimization?
What is the goal of lead optimization?
Signup and view all the answers
Study Notes
Divalent Atoms or Groups
- Examples of divalent atoms or groups include -CH2, -NH, -O-, and -S-.
- Procaine is a local anesthetic with membrane stabilizing properties that is rapidly hydrolyzed by esterase.
- Procainamide is less hydrolyzed by esterase.
Bioisosteres
- Bioisosteres are atoms or groups that have similar biological activity but differ in their chemical structure.
- Isosteric replacement aims to improve the activity of a class of biologically active compounds.
- Examples of classical bioisosteres include:
- Acetyl choline, which is hydrolyzed by esterase
- Carbachol, which is less hydrolyzed by esterase due to the resonance effect of the -NH2 group
- Lead compound Celecoxib has a COX-II IC50 of 0.04 μg, while the modified compound has a COX-II IC50 of 0.1 μg.
Non-Classical Bioisosteres
- Non-classical bioisosteres are atoms or groups that have similar biological activity but do not have apparent isosteric similarity.
- Classification of non-classical bioisosteres includes:
- Exchangeable groups, which have similar binding modes to the receptor
- Hydrophobic pocket vacant, which can be extended by adding an extra hydrophobic alkyl group
Optimizing Hydrophilic/Hydrophobic Properties
- Lipinski's rule of five states that a drug should have a molecular weight of less than 500, a log P value of less than 5, and fewer than 5 hydrogen bond donors.
- Hydrophilic drugs can be masked by:
- Adding an alkyl or acyl group to decrease polarity
- Forming esters or amides
- Hydrophobic drugs can be modified by:
- Adding a polar functional group to increase polarity
- Removing a polar functional group to decrease polarity
Steric Shields
- Steric shields are used to protect functional groups from chemical and enzymatic degradation.
- Examples include:
- Adding a bulky alkyl group close to the functional group
- The t-butyl group in the antirheumatic agent D-1927 serves as a steric shield and blocks hydrolysis of the terminal peptide bond
Lead Optimization
- Objectives of lead optimization include:
- Improving potency, toxicity, specificity, duration of action, ease of application, stability, and costs
- Approaches to lead optimization include:
- Simplification
- Rigidification
- Ring variation
- Structure extension
- Optimizing hydrophilic/hydrophobic properties
- Steric shields
- Bioisosteres
- Prodrug approach
Lead Optimization Approaches
- Structure simplification involves:
- Retaining the pharmacophore
- Removing unnecessary functional groups
- Removing excess rings
- Removing unnecessary asymmetric centers
- Advantages of structure simplification include:
- Easier, quicker, and cheaper synthesis
- Increased selectivity and decreased side effects
- Rigidification involves:
- Converting a flexible molecule into a rigid one
- Reducing the number of active conformations
- Increasing selectivity and reducing side effects
Studying That Suits You
Use AI to generate personalized quizzes and flashcards to suit your learning preferences.
Description
This quiz covers the importance of hydrophilic and hydrophobic properties in drug design, including the Lipinski rule of five and strategies for masking polar functional groups.