Drug Design Challenges and Strategies

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Questions and Answers

What role do N-Acylsulphonamides play in drug design?

N-Acylsulphonamides are used as bioisosteres for carboxylic acids in drug design.

How can steric shields protect drugs from hydrolysis?

Steric shields hinder the approach of nucleophiles or enzymes to susceptible functional groups.

What is the effect of replacing methyl with NH2 in an ethanoate ester?

Replacing methyl with NH2 results in a urethane functional group that is more stable than the ester.

Why are amides generally more resistant to hydrolysis than esters?

Amides are more resistant to hydrolysis because the lone pair of nitrogen stabilizes the carbonyl group, reducing its electrophilicity. Signup and view all the answers

What characteristics differentiate bioisosteres from isosteres?

Bioisosteres have similar biological activity while isosteres maintain similar physical or chemical properties. Signup and view all the answers

Provide an example of a drug that utilizes a steric shield for protection.

The anti-rheumatic agent D 1927 incorporates a t-butyl group as a steric shield. Signup and view all the answers

How does the electronic stabilization of a functional group influence drug design?

Electronic stabilization helps to prolong drug activity by making the functional group less susceptible to degradation. Signup and view all the answers

In what situations might replacing an ester with an amide be effective?

Replacing an ester with an amide may work effectively in certain categories of drugs that require stability against hydrolysis. Signup and view all the answers

What is one method of targeting drug delivery to rapidly dividing tumor cells?

Attaching the active drug to essential building block molecules like amino acids or nucleic acids. Signup and view all the answers

What role do monoclonal antibodies play in targeted cancer therapy?

Monoclonal antibodies can recognize unique tumor cell antigens and deliver attached drugs or poisons to kill the cells. Signup and view all the answers

Explain the concept of ADEPT in cancer treatment.

ADEPT involves an enzyme-antibody conjugate that activates an anticancer prodrug, directing the enzyme to the tumor. Signup and view all the answers

Why is it important to consider a binding region within the receptor binding site as an available volume?

It allows for flexibility in drug design, enabling the relevant binding group to be positioned in various locations within that volume. Signup and view all the answers

How can drugs be targeted to treat gastrointestinal infections without being absorbed into the bloodstream?

By using a fully ionized drug that cannot cross cell membranes, like highly ionized sulphonamides. Signup and view all the answers

What strategy can be used to target drugs to peripheral regions and avoid the CNS?

Increasing the polarity of drugs to reduce their ability to cross the blood-brain barrier. Signup and view all the answers

What potential issue arises when shifting a metabolically susceptible binding group?

It may make the molecule unrecognizable to both its target and the metabolic enzyme. Signup and view all the answers

What is a potential difficulty in designing drugs to selectively act on the CNS?

The drug must efficiently cross the blood-brain barrier while being rapidly metabolized in the peripheral system. Signup and view all the answers

How can varying a ring system enhance metabolic stability?

By adding a nitrogen atom to lower the electron density of the ring system. Signup and view all the answers

What is an example of a ring replacement that improves metabolic stability in antifungal agents?

Replacing the imidazole ring in tioconazole with a 1,2,4-triazole ring in fluconazole. Signup and view all the answers

Why is the uptake of building block molecules greater in tumor cells than in normal cells?

Tumor cells grow more quickly and require these building blocks in larger quantities due to their rapid division. Signup and view all the answers

What are some challenges associated with using targeted drug delivery systems?

Identifying suitable antigens and producing sufficient quantities of monoclonal antibodies can pose significant challenges. Signup and view all the answers

What can be done to stabilize electron-rich aromatic rings prone to oxidative metabolism?

Replacing them with nitrogen-containing heterocyclic rings like pyridine or by adding electron-withdrawing substituents. Signup and view all the answers

Why might substituents like methyl need to be retained in some drug structures despite their susceptibility to metabolism?

Methyl groups may play essential roles in binding affinity and activity of the drug. Signup and view all the answers

In the example of F13640, what was done to counteract the susceptibility of the methyl substituent on the pyridine ring?

The pyridine ring was changed to a pyrimidine ring to improve metabolic stability. Signup and view all the answers

What happens to the methyl substituent on the pyridine ring during metabolism according to the text?

It is oxidized and converted to a carboxylic acid, which is inactive. Signup and view all the answers

What is the significance of using ester prodrugs like enalapril?

Ester prodrugs like enalapril help improve membrane permeability for the active drug, enalaprilate, facilitating its therapeutic effects. Signup and view all the answers

How can modifying esters with electron-withdrawing groups affect their hydrolysis?

Introducing electron-withdrawing groups to esters can make them more susceptible to hydrolysis by stabilizing the alkoxide leaving group. Signup and view all the answers

Explain the role of N-methylated prodrugs in enhancing membrane permeability.

N-methylated prodrugs, like hexobarbitone, reduce polarity and improve lipid solubility, aiding in their membrane permeability. Signup and view all the answers

What is the 'Trojan horse' approach in drug design as exemplified by levodopa?

The 'Trojan horse' approach involves designing prodrugs, like levodopa, to exploit transport proteins for entrance through the cell membrane, enhancing drug delivery. Signup and view all the answers

Why is levodopa chosen as a prodrug despite its polar nature?

Levodopa, although polar, is recognized by amino acid transport proteins, allowing it to cross the blood-brain barrier to deliver dopamine effectively. Signup and view all the answers

What challenge does 6-mercaptopurine address when used as a prodrug?

6-mercaptopurine is designed to prolong its activity despite rapid elimination by the body, useful for immunosuppression. Signup and view all the answers

How can the chemical stability of ester prodrugs be maintained?

Ester prodrugs' stability can be maintained by ensuring they are not overly reactive to hydrolysis from stomach or intestinal conditions. Signup and view all the answers

What metabolic reaction occurs frequently in the liver and helps enhance the utility of certain prodrugs?

N-demethylation is a common metabolic reaction in the liver that reduces the polarity of polar amines, enhancing their membrane permeability. Signup and view all the answers

What is hetacillin and how does it function as a prodrug?

Hetacillin is a prodrug that locks up nitrogen in a ring structure, slowly decomposing to release ampicillin and acetone. Signup and view all the answers

What distinguishes a 'sleeping agent' from a conventional prodrug?

'Sleeping agents' remain inactive until activated by an external influence, while conventional prodrugs are metabolized in the body to their active forms. Signup and view all the answers

Why are endogenous compounds considered for use as drugs?

Endogenous compounds, like hormones, occur naturally in the body and could provide effective treatment without the drawbacks of synthetic drugs. Signup and view all the answers

What challenges exist when considering the use of neurotransmitters as drugs?

Many neurotransmitters are unstable in the stomach and would break down quickly or be inactivated by enzymes if injected into the bloodstream. Signup and view all the answers

How do photosensitizing agents work in cancer treatment?

Photosensitizing agents, when irradiated with light, convert to an excited state and produce toxic singlet oxygen that can kill cancer cells. Signup and view all the answers

What does the term 'prodrug' refer to in the context of pharmacology?

A prodrug is an inactive compound that requires metabolic conversion in the body to become an active pharmacological agent. Signup and view all the answers

Why might administered dopamine not correct a dopamine shortage in the brain?

Administered dopamine is unstable, may not reach its target receptors, and would be quickly inactivated by the body's mechanisms. Signup and view all the answers

Discuss the significance of neurotransmitters in drug development.

Neurotransmitters are crucial for communication between nerve cells, but their instability and rapid inactivation complicate their use in drug development. Signup and view all the answers

What is the significance of PEGylation for proteins in relation to kidney filtration?

PEGylation increases the size of proteins, preventing them from being filtered into the kidney nephrons and allowing them to remain in the bloodstream. Signup and view all the answers

How do PEG molecules benefit proteins like L-asparaginase and adenosine deaminase?

PEG molecules act as a hydrophilic shield that protects the proteins and reduces their immunogenicity, leading to longer plasma half-lives. Signup and view all the answers

What condition is associated with a lack of adenosine deaminase and how is it treated?

Severe Combined Immunodeficiency (SCID) is associated with a lack of adenosine deaminase, and it is treated with PEGylated forms of the enzyme called pegademase. Signup and view all the answers

What is peginteferon a2b used for and how is it derived?

Peginterferon a2b is used for the treatment of hepatitis C and is derived from PEGylated interferon. Signup and view all the answers

What role do antibodies play in targeting cancer cells?

Antibodies can recognize specific antigens on cancer cells, enabling them to target and bind to those cells for therapeutic purposes. Signup and view all the answers

What organism is primarily used to produce murine antibodies?

Mice are primarily used to produce murine antibodies by exposing them to specific antigens. Signup and view all the answers

Explain the process of creating hybridomas from mouse B lymphocytes.

Hybridomas are created by fusing mouse B lymphocytes that produce desired antibodies with immortal human B lymphocytes. Signup and view all the answers

What is the main advantage of monoclonal antibodies over polyclonal antibodies?

Monoclonal antibodies are identical copies of a single type of antibody, providing consistency and specificity in targeting. Signup and view all the answers

Study Notes

Drug Design: Optimizing Access to the Target

Drug design strategies aim to optimize binding interactions between drugs and their targets.
The best binding interactions don't always equate to the best drug.
Drugs must overcome barriers to reach their target in the body.
Strategies for overcoming these barriers involve modifying the drug itself.
Drug-polymer or antibody linking, or encapsulation within a polymeric carrier, aids drug delivery.
The ultimate goal is for drugs to be effectively absorbed, reach targets, remain stable during transit, and be eliminated efficiently.
This is encompassed by a drug's pharmacokinetics.

Optimizing Hydrophilic or Hydrophobic Properties

Drug hydrophilicity/hydrophobicity impacts solubility, absorption, distribution, metabolism, and excretion (ADME).
Too polar or hydrophilic drugs poorly cross gut wall cell membranes.
Injection might be required for these drugs.
They tend to bind to plasma proteins, be prone to metabolic conjugation, and quickly excreted.
Highly hydrophobic drugs face similar challenges with poor absorption when taken orally.
Toxic metabolites are more likely to form from hydrophobic drugs.

Measuring Hydrophobicity

Hydrophobicity can be experimentally measured by testing the drug's relative distribution in an n-octanol/water mixture.
Hydrophobic molecules prefer the n-octanol layer, while hydrophilic molecules prefer the aqueous layer.
The relative distribution is the partition coefficient (P).
The equation for calculating P is P = [Drug concentration in octanol]/[Drug concentration in aqueous solution].
Log P values are more commonly used to express hydrophobicity.
High log P values indicate hydrophobicity, while low values indicate hydrophilicity.

Varying Polar Functional Groups

Many drugs exist as an equilibrium between ionized and un-ionized forms.
Log P measures only the relative distribution of un-ionized species between water and octanol.
The relative distribution of all species is given by log D.
Drug absorption and oral bioavailability are not solely determined by hydrophilic/hydrophobic properties.
Molecular flexibility also plays an important role.
Masking polar groups (alcohols, phenols, carboxylic acids, amines) with alkyl or acyl groups can decrease polarity and improve absorption.
These masks can be temporary to prevent interference with binding targets.

Adding or Removing Polar Functional Groups

Polar groups can be added to increase polarity.
For instance, antifungal agent tioconazole has become more polar and orally active as fluconazole.
Nitrogen-containing heterocycles, such as morpholine or pyridine, can be incorporated to improve polarity and water solubility.
Removal of polar functional groups can also help decrease polarity. This is particularly effective when used in conjunction with natural lead compounds.

Varying Hydrophobic Substituents

Polarity can be altered by adding, removing or modifying hydrophobic substituents.
Extra alkyl groups can increase hydrophobicity.
Larger alkyl groups can sometimes replace smaller.
This concept also works in reverse and smaller alkyl groups may replace larger ones.
A methylene shuffle can be used to modify hydrophobicity.
Halogen substitutions (e.g., chloro, fluoro) also improve hydrophobicity.

Varying N-Alkyl Substituents

Drug pKa values outside the 6-9 range are poorly absorbed through cell membranes.
Varying N-alkyl substituents can often alter pKa to a suitable range.
Increased N-alkyl groups can increase electron-donating, increasing basicity.
Increased steric bulk around the nitrogen atom from increased alkyl group size may decrease basicity.
These two effects often oppose each other.

Varying Aromatic Substituents

By adding electron-donating or electron-withdrawing substituents to an aromatic ring, this can be used to adjust pKa values of aromatic amines or carboxylic acids.
Substituent positions (relative to the amine or carboxylic acid) affect interactions with the ring, such as resonance.

Bioisosteres for Polar Groups

Bioisosteres replace functional groups with similar properties to improve pharmacokinetics.
Often utilized to replace carboxylic acid groups with a 5-substituted tetrazole ring, as this is often a more stable configuration.
This is particularly beneficial when used in place of carboxylic acids which have potential ionization issues.

Making Drugs More Resistant to Degradation

Strategies exist for making drugs more resistant to hydrolysis and drug metabolism.
Steric shielding is a common strategy that hinders the attack from nucleophiles or enzymes.
A bulky alkyl group (e.g., tert-butyl) is used close to the functional group to act as a shield.
Electronic effects of bioisosteres stabilize a labile functional group. Examples include switching from esters to amides.
This process improves the stability of a medication.

Metabolic Blockers

Some drugs are metabolized by introducing polar groups at specific positions in their structure.
The introduction of a polar group can create polar conjugates that are quickly eliminated.
By introducing a methyl group at the susceptible position, this process of metabolism can be blocked, prolonging the drug's activity.

Removal or Replacement of Susceptible Metabolic Groups

Certain chemical groups and their metabolites are susceptible to metabolic enzymes.
Methyl groups on aromatic rings are often oxidized to carboxylic acids, which are quickly eliminated.
Other susceptible groups for metabolism include: aliphatic and aromatic C-hydroxylations, N-and S-oxidations, O- and S-dealkylations, and deaminations.
Susceptible groups such as methyl groups on aromatic rings may be replaced with more stable groups such as chloro group to increase drug lifespan.

Group Shifts

Removing or replacing a vulnerable group is feasible if it’s not involved with binding interactions.
Masking vulnerable groups temporarily: use prodrugs
Shifting the vulnerable group within the molecular structure can improve stability.

Ring Variation and Ring Substituents

Certain ring systems can be susceptible to metabolism.
Adding nitrogens into rings can reduce electron density and improve stability
Replace electron-rich functional groups (e.g., phenyl groups) with nitrogen-containing heterocycles, such as pyridine or pyrimidine, for improved stability.
Varying aromatic substituent positions alter the metabolic resistance and toxicity profile.

Making Drugs Less Resistant to Drug Metabolism

Drugs that are too stable to metabolism or are slowly excreted can pose problems.
Strategies to reduce stability is to introduce metabolically susceptible groups thus shortening drug lifespan.
Introducing groups for metabolism can help decrease drug lifespan or avoid/minimize side effects from potential metabolites which may also cause problems.

Self-Destruct Drugs

Self-destruct drugs are chemically stable under one condition, but become unstable under another.
This instability can result in quicker inactive drug turnover in the body.
For example, the neuromuscular blocking agent atracurium is stable at an acidic pH, but self-destructs when exposed to alkaline conditions in the blood.

Targeting Drugs

Targeting drugs to specific locations improves efficacy and reduces side effects.
Design drugs to use specific cellular transport systems.
Attaching the active drug to crucial 'building block' molecules, such as amino acid or nucleic acids, to target tumour cells.
Attaching drugs to monoclonal antibodies that recognize tumour antigens.

Targeting Gastrointestinal Infections

To prevent absorption into the blood supply, ionized drugs are used against gastrointestinal infections.
Ionized drugs are poorly absorbed into the bloodstream and thus increase the likelihood of the drug remaining in the GI tract.

Targeting Peripheral Regions

Targeting drugs to peripheral locations rather than the central nervous system (CNS) reduces the likelihood of side effects from crossing the blood-brain barrier.
Increasing polarity of drugs can reduce their ability to cross this barrier.

Targeting with Membrane Tethers

Membrane tethers can anchor drugs to cell membranes.
This process is useful for drugs to directly affect receptors on cell membranes.

Reducing Toxicity

Drugs can fail clinical trials due to toxic side effects, which can come from toxic metabolites produced during metabolism.
Making the drug more resistant to metabolic enzymes can prevent the formation of toxic metabolites.
Modification (substituent position/substituent itself) to prevent toxic product formation is a valuable strategy.

Prodrugs

Prodrugs are inactive compounds converted into active drugs within the body via metabolic enzymes.
Prodrugs are helpful when an active drug is unstable or has issues with crossing body membranes.
Prodrugs can also be useful in preventing adverse side-effects from the drug or to improve membrane permeability.

Prodrugs to Improve Membrane Permeability

Prodrugs are often used to temporarily mask functional groups which hinder their transport across membranes.
Frequently involves using esters to mask a carboxylic acid to allow the molecule to pass through membranes more readily.

N-methylated Prodrugs

N-methylation is a common metabolic reaction in the liver, to improve membrane permeability of polar amines.
Several hypnotics, and anti-epileptics use this approach.

Trojan Horse Approach

Prodrugs can be used in combination with natural transport proteins to transport drugs to specific targets, such as in the treatment of Parkinson’s disease.

Prodrugs to Prolong Drug Activity

Prodrugs are designed to be converted slowly into the active drug.
This strategy prolongs the drug activity in the body.
For example, 6-mercaptopurine and azathioprine can both suppress the body’s immune response.

Prodrugs to Increase Chemical Stability

Drugs decompose in solution due to intramolecular reactions, such as ampicillin.
Prodrugs are used to prevent this intramolecular reaction from occurring.
For example, hetacillin can be used to stop such reactions from happening in ampicillin.

Prodrugs Activated by External Influence

Inactive compounds that only become active via external influence (light, for example).
This is a useful drug design for treating certain cancers, for example.

Endogenous Compounds as Drugs

Endogenous compounds include hormones, neurotransmitters, peptides, proteins and antibodies.
Their function in the body (and the body’s ability to safely regulate their mechanisms for such function) makes them viable components for use as drugs.

Neurotransmitters

Neurotransmitters are often unstable in their current form and therefore aren’t easily used in medicine.
The instability means their activity is short-lived and they would either have to be modified or would react poorly in the body.

Natural Hormones, Peptides, and Proteins as Drugs

Natural hormones, peptides, proteins, already circulate in the body, and thus are promising candidates for drug development.
Adrenaline is a good example, treating allergic reactions.
Insulin and other proteins help regulate a variety of processes in the body.

Antibodies as Drugs

Antibodies can recognize specific molecules, thus are useful for directing drugs or poisons to specific targets.
Monoclonal antibodies are created to generate a larger quantity of the same identical antibody.
Humanized monoclonal antibodies reduce the 'foreign' nature of the antibody to the body and prevent harmful side-effects.

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Description

Explore the intricate world of drug design with this quiz that delves into the roles of various chemical compounds and strategies used in developing effective medications. From the protective mechanisms of steric shields to the significance of electronic stabilization and targeted drug delivery, this quiz covers crucial topics in pharmaceutical chemistry. Test your knowledge on how modifications of functional groups are employed to enhance drug efficacy.