Drug Design Strategies

Question 1

Xenobiotic definition

Answer 1

Xeno=foreign

Biotic=substance

Question 2

Dissociation constant (Kd)

Answer 2

Concentration of drug that gives 50% receptor occupancy

Equal to 1/Keq

Question 3

Small Kd values indicate…

Answer 3

A tight-binding drug-receptor interaction

Question 4

Agonist

Answer 4

Binds to receptor and mimics the effect of the endogenous ligand (natural substance)

Question 5

Antagonist

Answer 5

Binds to receptor but gives no biological effect (blocks binding of agonists to the receptor)

Question 6

Partial agonist

Answer 6

An agonist that doesn’t give maximal effect at saturation

Question 7

Inverse agonist

Answer 7

Binds to receptor and gives an effect which is opposite to an agonist (rare)

Question 8

Solubility of drugs

Answer 8

Drugs need to be partially water soluble (living cells are an aqueous environment) as well as partially fat soluble (living cells are surrounded by lipid bilayers)

Question 9

Partition coefficient between water and n-octanol

Answer 9

Most common measure of hydrophobicity
log P= log (drug in octanol/drug in water)
log P=0, then drug is equally soluble in water and octanol

Question 10

Prodrugs

Answer 10

Compounds that are inactive in their native form but are easily metabolized to the active agent
Allow for usage of drug at proper time

Question 11

First-pass effect

Answer 11

Oral drugs are transported to the liver

Injectable drugs bypass this

Question 12

Therapeutic window

Answer 12

Window between drug effectiveness and bad effects

Want about 3 log folds

Question 13

Bronsted-Lowry acid vs. Bronsted-Lowry base

Answer 13

Acid: Proton donor
Base: Proton acceptor

Question 14

Quantitative structure-activity relationship (QSAR)

Answer 14

Predicting the degree that a molecule will exhibit physiological effects

Question 15

QSAR models

Answer 15

Plotting physiological response vs. a molecular trait (partition coefficient, etc.)
Type of model that fits data sometimes indicates the mechanistic details of the physiological response

Question 16

Comparative molecular field analysis (CoMFA)

Answer 16

3-D QSAR

Aligning structures of drugs and comparing their effects: understanding what portions of drugs do

Question 17

Conformational analysis

Answer 17

Method used to understand compound's bioactive conformation
# of conformers = (360/angle increment)^# of rotatable bonds

Question 18

Isosteres

Answer 18

Different functional groups that may be interchangeable

Similar steric, electronic, and solubility characteristics

Question 19

Lipinski rule of 5

Answer 19

Candidate molecule is more likely to have poor absorption or permeability if:
1. Molecular weight exceeds 500
2. Calculated log P exceeds 5
3. More than 5 H-bond donors
4. More than 10 H-bond acceptors
Doesn’t apply to majority of natural products

Question 20

High-thoroughput screening

Answer 20

Looking for specific functions of drugs using both computational and in vitro methods