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Questions and Answers
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 result of replacing a carboxylate group with an amino group in Carbachol?
What is the purpose of bioisosteric replacement in drug design?
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What is the effect of adding a polar functional group to a drug molecule?
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Which of the following is an example of an isostere?
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What is the primary goal of optimizing hydrophilic/hydrophobic properties of a drug?
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Which of the following is an example of masking a polar functional group to decrease polarity?
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What is the purpose of adding a bulky alkyl group to a drug?
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What is the effect of adding a polar functional group to a hydrophobic drug?
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What is the purpose of the Lipinski rule of five?
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What is the result of introducing a polar hydroxyl group and more polar heterocyclic rings to a drug?
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What is the main reason for simplifying the structure of a lead compound?
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Which of the following is an advantage of rigidification?
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What is bioisosterism?
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What is the purpose of steric shields?
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What is the result of adding a polar functional group to a molecule?
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What is the goal of lead optimization?
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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
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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.
