drug design and toxicity?

What are the roles and contributions to binding energy

Charge interactions (salt bridges)

• H-bond donors and acceptors (HBD/HBA)

• Charge interactions (salt bridges): Strong electrostatic attraction; high binding energy.

• H-bond donors/acceptors (HBD/HBA): Directional bonds; moderate binding energy; increase specificity.

What are the roles and contributions to binding energy of:

• Aromatic stacking

• Hydrophobic interactions

• Aromatic stacking: π–π interactions between rings; moderate contribution; stabilizes positioning.

• Hydrophobic interactions: Nonpolar groups cluster to avoid water; major contribution; entropy-driven.

What is the pharmacophore concept and its significance in drug design?

• Defines the relative positions of key groups involved in binding.

• Derived from an active conformation of the molecule.

• Enables lead hopping: moving from one chemical structure to a different one while retaining activity.

what are the different concepts for modifying molecules ?

-simplification concept
-rigidification

What is the Simplification Concept in drug design and why is it useful?

• Natural lead compounds are often complex and hard to synthesize.

• Simplifying makes analogues easier, quicker, and cheaper to make.

• Simpler structures may fit binding sites better and increase activity.

• Removing excess functional groups can improve selectivity and reduce toxicity.

oversimplification may result in

decreased activity + selectivity

simpler molecules have more ... and are more likely to .....

conformation
more likely to interact with more than 1 target binding site

What is rigidification in drug design and its effects?

• Flexible endogenous leads (e.g., adrenaline) can bind multiple targets.

• Rigidify to limit conformations (conformational restraint).

• Increases activity (more chance of desired conformation).

• Increases selectivity (less chance of undesired conformation).

• May make molecule more complex and harder to synthesize.

pharmacokinetic drug design looks at approaches to affecting the ... and ...

-absorption of a drug
-coping with metabolism/ isosteres/bioisosteres

What are key solubility and polarity requirements for drugs?

• Polar: soluble in water, interact with targets.

• Lipophilic (“fatty”): cross membranes, avoid rapid excretion.

• Balanced: drugs need both hydrophilic and lipophilic properties.

How can drug permeability be modified, what are the disadvantages, and what methods are used?

• Modification: Vary alkyl group size → larger groups increase hydrophobicity.

• Disadvantage: May interfere with target binding (steric hindrance).

• Methods:

  • Change alkyls on heteroatoms → feasible.

  • Change alkyls on carbon skeleton → difficult, often requires full synthesis.

Why is increased hydrophobicity beneficial for drugs?

• Improves membrane permeability=which are largely lipid (fatty) in nature.

• Reduces rapid excretion=increasing bioavibilty

• Must be balanced with aqueous solubility=so can still dissolve in aqeous envrioenemnt

What is the rationale and disadvantage of masking or removing polar groups in drug design?

• Rationale: decreases polarity → increases hydrophobicity

• Disadvantages:

  • Polar group may be needed for target binding

  • Unnecessary polar groups often already removed during simplification

What is the effect and rationale of adding polar groups to a drug?

• Effect: increases polarity, decreases hydrophobicity

• Rationale / Uses:

  • Reduce gut absorption (useful for gut-targeted drugs)

  • Limit CNS side effects

  • Limited by gut transport time

How does modifying the pKa of a drug affect its absorption?

• Varying pKa changes the percentage of ionised drug.

• Ionised drugs are generally poorly absorbed and too water-soluble.

How can pKa be modified in amines to influence drug properties?

• Modify alkyl substituents on amine nitrogen (electron-withdrawing groups decrease basicity).

• Modify aryl substituents on aromatic amines (electron-withdrawing groups make the amine less basic).

How can metabolic stability of a drug be improved?

• Introduce bulky groups as a steric shield.

• Protect susceptible functional groups (e.g., esters) from hydrolysis.

• Hinders attack by nucleophiles or metabolizing enzymes.

How are steric and electronic effects combined to improve drug stability?

• Steric shielding + electronic stabilization used together.

• Increases both chemical and metabolic stability of the molecule.

What are isosteres in drug design?

• Rational variation of a functional group.

• Maintain similar size, shape, and electronic properties.

What are bioisosteres and why are they used in drug design?

• Replace a susceptible group with a different group without affecting activity.

• Can improve pharmacokinetic properties.

• Not necessarily structurally identical to the original group; may look quite different.

How can metabolism of drugs be blocked to increase stability?

• Drugs are metabolized at specific susceptible sites.

• Introduce blocking groups at these sites.

• Increases metabolic stability and drug lifetime.

How can labile groups in drugs be replaced to improve metabolic stability?

• Metabolism often occurs at specific susceptible groups.

• Remove or replace these groups with metabolically stable groups

• Alternatively, move the metabolic target to a less critical position.

What is a pro-drug and how is it activated?

• Inactive compound converted to an active drug in the body.

• Activation often occurs via metabolic or mechanistic events.

What are the main uses of pro-drugs in drug design?

• Improve membrane permeability

• Prolong activity

• Mask toxicity and side effects

• Adjust water solubility

• Enable drug targeting

• Improve chemical stability

How are carboxylic acids masked in pro-drugs, and what are key considerations?

• Mask polar/ionisable carboxylic acids.

• Hydrolysed in blood by esterases to release active drug.

• Carboxylic acid required for target binding.

• Leaving group (alcohol) should be non-toxic.

• Example: Enalapril → Enalaprilate (antihypertensive).

What is the rationale behind anti-drugs?

• Designed to decrease metabolic stability and shorten drug lifetime.

• Useful for drugs that linger too long and cause side effects.

How are anti-drugs designed and what is an example?

• Add groups susceptible to Phase I or Phase II metabolism.

• Example: Anti-arthritic agents with shortened in vivo lifetime.

How does the diazepam prodrug LDZ reduce side effects?

• LDZ is a prodrug of diazepam.

• Avoids high initial plasma levels.

• Reduces drowsiness side effects associated with regular diazepam.