Drug Design Challenges and Strategies

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.

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.