CHEM 455

Question 1

Lead Compound

Answer 1

prototype having desired activity but with some undesirable characteristics that can be modified by synthesis to amplify activity or minimize undesirable properties

Question 2

properties of a good lead

Answer 2

1. interacts with desired target
2. amenable to synthetic modifications
3. possesses physical properties consistent with ability to reach target after administration

Question 3

sources of lead compounds

Answer 3

natural ligands/substrates or another substance already known to interact with target of interest

Question 4

screening

Answer 4

conducting a biological assay on large collection of compounds to identify compounds that have desired activity

Question 5

random screening

Answer 5

no effort to bias set of screened compounds based on prior knowledge of target or known ligands

Question 6

targeted screening

Answer 6

some prior knowledge to select compounds that are most likely to interact with target

Question 7

fragment based screening

Answer 7

methods using xray crys. or NMR to identify simple molecules w modest affinity for a target w intent of connecting 2 or more fragments to create useful lead

Question 8

ADME

Answer 8

absorption, distribution, metabolism, excretion

Question 9

Absorption

Answer 9

process by which drug reaches bloodstream from site of administration

Question 10

Distribution

Answer 10

to which “compartments” in body the drug goes

ex: some stay in bloodstream and some in tissues

Question 11

Metabolism

Answer 11

action of specific enzymes on a drug to convert it to one or more new molecules called metabolites (can be favorable or unfavorable)

Question 12

Excretion

Answer 12

means by which body eliminates an unchanged drug or metabolites

Question 13

potency

Answer 13

strength of biological effect

Question 14

selectivity

Answer 14

unintended sites of action

Question 15

How to conduct SAR study

Answer 15

make single variable changes to molecule and track potency and other features to improve molecule and determine pharmacophore

Question 16

How to determine pharmacophore

Answer 16

find activity cliffs to determine interactions between molecule and target

Question 17

types of interactions involved in recognition/binding between ligand and enzyme receptor

Answer 17

• ionic interactions
• ion-dipole
• dipole-dipole
• H bonding
• charge-transfer complex
• hydrophobic
• cation-pi
• halogen bonding
• van der waal

Question 18

efficacy vs affinity

Answer 18

efficacy - measure of max bio effect that drug can produce as a result of receptor binding
affinity - measure how strongly the drug binds to its receptor

Question 19

Lipinski’s rule of 5 for POOR bioavailability

Answer 19

if they have 2 OR MORE of following characteristics then it's POOR:
MW > 500 da
log P > 5
>5 H bond donors (OH+NH)
>10 H bond acceptors (N+O)

Question 20

Veber’s Rules

Answer 20

poor bioavailability result from:
rotatable bonds > 10
high polar surface area >140A^2
total H bonds > 12 donors & acceptors

Question 21

common off-targets

Answer 21

related family members, cytochrome P450 enzymes, specific transporters, hERG channel

Question 22

Toxicophores

Answer 22

functional groups that have undesirable effects and functional groups that can be converted by metabolic processes to moieties that have undesirable effects

Question 23

basic types of toxicophores

Answer 23

aromatic nitro, anilines, epoxides, aziridines, nitroso, azo, aliphatic halides, heteroatom-heteroatom bonds, polycyclic aromatic systems, imidazole

Question 24

functional groups that become toxicophores after metabolism

Answer 24

furans & thiophenes –> epoxides
thioamides & thioureas –> electrophilic imines
anilines –> electrophilic nitroso derivatives

Question 25

Clinical trials phases

Answer 25

Phase 0- exploratory, 10-15 healthy subjects to gather prelim human ADME data
Phase 1- evaluates safety, tolerability. 20-100 healthy volunteers unless life threatening
Phase 2- assesses effectiveness, determines side effects. few hundred diseased patients. 1-3 years
Phase 3- establishes efficacy of drug in several thousand patients. 2-6 years
Phase 4- drug is on market and assessed for real safety and tolerability. millions have taken drug

Question 26

Pharmacodynamics

Answer 26

receptor interactions; effects of drug, potency and mechanism of action

Question 27

Pharmacokinetics

Answer 27

depends on water solubility and lipid solubility; ADME

movement of drugs within body

Question 28

types of modifications to lead compound

Answer 28

homologation, chain branching, bioisosterism, conformational constraint

Question 29

Homologation

Answer 29

increasing compounds by a constant unit

Question 30

Chain Branching

Answer 30

lowers potency if lipophilicity is important and can interfere with receptor binding

Question 31

Bioisosterism

Answer 31

substituents or groups with chemical or physical similarities that produce similar biological properties
effects: structural, receptor interactions, pharmacokinetics, metabolism

Question 32

Conformational Constraint

Answer 32

1. if constraint retains bio activity then most likely approximates bioactive conformation
2. help differentiate desired target from other proteins
3. can say something about physical properties of receptor

Question 33

Classic bioisosteres

Answer 33

peripheral layer of electrons are considered identical

Question 34

Non-classic bioisosteres

Answer 34

do not have same # of atoms; do not fit steric/electronic rules of classic isosteres

Question 35

Advantages of Computer Based Design

Answer 35

1. proteins can be visualized in 3D
2. structure can be manipulated
3. binding site enlarged
4. physiochemical properties of each part of receptor can be viewed
5. distances between groups can be determined
6. small molecules can be docked to determine their fit

Question 36

Disadvantages of Computer Based Design

Answer 36

1. XRay/NMR structure required
2. Crystals obtained by crystallization of proteins happens under nonphysiological conditions
3. crystal structures represent the most stable conformation but don’t predict what it will be in a living cell
4. if binding ligand results in a conformational change, it is unlikely that it will occur in crystalline state
5. proteins are more dynamic than rigid
6. resolution is not perfect
7. ligand does not have to bind in lowest energy conformation
8. different geometries can have the same conformational energy but with different shapes

Question 37

Importance of flexibility and conformation

Answer 37

receptors & proteins are flexible – sometimes lowest energy conformation of drug won’t necessarily bind to active site of receptor

Question 38

intellectual property position

Answer 38

obtaining a patent on a drug in order to recover costs of drug discovery