Drug Likeness + Druggability

What are the four key areas evaluated in early drug discovery?

Drug-target interaction, pharmacodynamics, pharmacokinetics, and toxicology.

What does SAR stand for in drug discovery?

Structure-Activity Relationships.

What equation relates binding energy (ΔG) to the dissociation constant (Kd)?

ΔG = RT ln Kd

What factors contribute to the binding energy between drug and target?

Desolvation, motion, configuration, and direct interaction energies.

What is the role of hydrogen bond donors (HBD) and acceptors (HBA) in drug binding?

Form key interactions with target binding sites to stabilize drug binding.

Why are esters often used in drug design?

As prodrugs to mask polar groups and improve membrane permeability.

Why can't tertiary amines act as hydrogen bond donors?

They have no available hydrogen atoms to donate.

What effect does N-methylation have on a drug molecule?

Prevents HBD interaction and introduces steric hindrance.

What are problematic functional groups often avoided in drug design?

Nitro groups, alkyl halides, acid chlorides.

What role do aromatic rings play in drug binding?

Hydrophobic interactions and π-π stacking.

How does alkyl chain variation affect drug design?

Tests binding pocket space and affects hydrophobic interactions.

What type of bonding is common with carboxylic acids?

Ionic bonding and hydrogen bonding.

What is the effect of ester hydrolysis on drug properties?

Increases polarity and may reduce target accessibility.

What binding mechanism is associated with free base amines?

Hydrogen bonding as both HBD and HBA.

Why are heteroaromatic analogues often used in drug design?

To fine-tune electronic properties and enhance binding.

What happens to binding energy if the Kd value increases?

Binding energy (ΔG) becomes less negative (binding weakens).

What kind of interaction is salt bridge formation?

Ionic interaction between charged groups.

What is the impact of a steric shield on drug binding?

Hinders binding interactions like HBA or HBD.

Which functional groups are typically strong hydrogen bond acceptors?

Ethers, aldehydes, ketones, esters.

What are the two effects of alkylation on a molecule?

Increased hydrophobicity and steric hindrance.

How can prodrugs improve drug pharmacokinetics?

By enhancing membrane permeability or stability.

Why is excessive aromaticity problematic in drug design?

Leads to high logP, molecular weight, and poor solubility.

What happens if esters are hydrolyzed too early in the bloodstream?

Drug activation may be compromised before reaching the target.

What property makes carboxylate groups strong binders?

They are charged and excellent hydrogen bond acceptors.

What binding feature do aldehydes and ketones offer?

They participate in dipole-dipole and hydrogen bonding interactions.

What interaction is common for amines with binding sites?

Ionic bonding and hydrogen bonding.

What is the effect of stereochemistry change from planar to tetrahedral?

May alter binding by changing the spatial orientation of key atoms.

Why are esters important as 'masking groups'?

They allow polar drugs to cross lipid membranes more easily.

What is the role of van der Waals forces in drug binding?

Facilitate weak but significant hydrophobic interactions.

What type of drugs use alkyl halides to covalently bond to targets?

Anticancer drugs.

What happens when a tertiary amide undergoes N-methylation?

Loss of HBD potential and increased steric hindrance.

Why is LiAlH4 used in drug analogue synthesis?

To reduce carbonyl compounds to alcohols.

What does DMPK stand for?

Drug Metabolism and Pharmacokinetics.

What is the meaning of 'prodrug'?

An inactive form of a drug that becomes active after metabolic conversion.

How do hydrogen bonds influence drug-target binding affinity?

By stabilizing the interaction and lowering the free energy (ΔG).

What functional groups serve both as HBD and HBA?

Water, alcohols, primary and secondary amines.