IC9 Molecular Drug Targets and Therapeutic Actions

Question 1

Is warfarin neutral/acidic/basic? Link to the chemical structure. Will it have a charge?

Answer 1

• acidic, can be deprotonated in physio pH → anionic, forms Na salt
  o enol, pair of e on -OH can delocalise into the conjugated system (vinyl group) → stabilised → lose H+ to form anion
  o ketone conjugated to the alkene and anion further stabilises it

Question 2

What tautomerism does phenindione have?

Answer 2

keto-enol tautomerism

Question 3

Which warfarin enantiomer is active? Which direction is linked to S and R?

Answer 3

• racemate, has a chiral centre
  o S and R identification
  o 1) put lowest priority grp at the back
  o 2) Compare the C, see what atoms are attached to it
  o 3) O > C > H etc.
  o Anticlockwise is S, clockwise is R

Question 4

How does warfarin form a hemiketal?

Answer 4

• hemiketal
  o OH attacked the C in the C=O, intramolecular bonding
  o Hemiketal is stable becos it’s in a 6-membered ring, where the conformation is staggered, angles are ideal and does not lead to ring strain

Question 5

What is the active and inactive forms of vit K?
What happens to them when warfarin is taken?

Answer 5

• Vitamin K hydroquinone (active) oxidised to epoxide (inactive)
• Warfarin will bind to VKORC1 and VKR → prevent epoxide from being reduced to hydroquinone

Question 6

What is the basic chemical structure that warfarin has?

Answer 6

Coumarin chemical structure:

• **lactone ring **
• usually have substituents at position 3 & 4

Question 7

What is the basic chemical structure that phenindione has?

Answer 7

Indane chemical structure:
- fused bicyclic hydrocarbon ring
- 2 ketone groups at position 1 and 3

Question 8

Which functional grp in phenindione gives it its ACG activity?
Why does phenindione have cross reactivity with warfarin?
Is phenindione neutral/acidic/basic?

Answer 8

Phenindione chemical structure + nature:

• Phenyl ring at position 2 gives ACG activity
• Cross reactivity with warfarin
  o Can form enol (acidic) and anion at physio pH
  o Structurally similar, thus bind to the same target
• acidic → have vinyl group

Question 9

Why is dabigatran metabolised by esterase?

Answer 9

Dabigatran etexilate chemical structure + nature:

• non-peptidomimetic prodrug (ester)
• activated by esterase

Question 10

Is Dabigatran neutral/acidic/basic?
Why?

Answer 10

• Dabigatran
  o Basic due to the amidine group (2 N atoms), LPE can move from 1 N to the other (similar to -COO), thus very stable and makes it a strong base

Question 11

Why is there a difference in the cLogP values for the prodrug and active metabolite of dabigatran?

Answer 11

• Dabigatran cLogP = 0.79 VS Dabigatran etexilate cLogP = 3.8 (more lipophilic due to the alkyl groups in the ester prodrug)

Question 12

What are the functional groups in rivaroxaban and the interactions that allows it to bind well? (5)

Answer 12

Rivaroxaban chemical structure + bond:

1. Morpholinone – hydrophobic interaction
2. O and N – H bond
3. Substitution of H on benzene ring will reduce activity (thus just want a clean benzene ring)
4. S-enantiomer required
5. 5-chlorothiophen has better activity than 6-chlorobenzene in a hydrophobic pocket – hydrophobic interaction

Question 13

How does aspirin bind to its target?

Answer 13

Aspirin MOA:

• Binds irreversibly to COX-1, by acetylating Ser residue
  –> inhibit production of thromboxane A2

Question 14

What is the MOA of clopidogrel?

Answer 14

Clopidogrel Chemical structure + MOA:

• Has thienopyridine
• Hydrolyzed ester to COOH (inactive)
• Oxidized thiophene in the thienopyridine to thiolactone (enone) by CYP3A4
  → thiolactone hydrolyzed to thiol & acid (ring opening, active)
  → thiol forms disulphide bonds with Cys in P2Y12

Question 15

What effect does paracetamol have and what target does it bind to?

Answer 15

Paracetamol activity + MOA:

• Antipyretic → inhibits COX-3 and thus production of prostaglandins in CNS
• Analgesics

Question 16

Why is paracetamol not recommended in the long run?

Answer 16

Paracetamol toxicity:

• Not recommended for long use –> NAPQI cause hepatotoxicity

Question 17

Is paracetamol neutral/acidic/basic?
What is the water solubility of paracetamol?

Answer 17

Paracetamol nature:

• Weakly acidic pKa 9.5 (due to phenol)
• Low water solubility

Question 18

Which part of the aspirin structure is important for anti-inflammatory effect?

Answer 18

Aspirin MOA + chemical structure:

• Anti-inflammatory
• Covalently acetylates Ser530 in COX-1, thus block PG synthesis
• OH ortho to COOH is impt
• 2nd phenyl ring conjugated to phenyl ring in salicylic acid increase anti-inflammatory activity

Question 19

What are the key components in the arylalkanoic acid (NSAIDs)?

Answer 19

General chemical structure:

• Phenyl/aromatic heterocyclic ring attached to COOH
• Calpha might hold CH3 –> making it chiral –> usually S-enantiomer is active
• Aryl and heteroarylacetic acid / aryl and heteroarylpropionic acid

Question 20

What are the important components of the indomethacin (NSAID) structure that allows for binding?

Answer 20

Chemical structure:

1. Only the acetic group is active
   a. COOH → ionizes and interacts with Arg120 in COX (ionic bond)
2. Adding CH3 to the Calpha in acetic group makes the S enantiomer active only
3. Aracylation (adding acyl CH3C=O-) is impt, replacing C=O on it reduces activity
4. CL and other lipophilic groups on aracylation retains activity
5. 2-Me groups fit into small hydrophobic pockets → produce steric hindrance → pushes the 4-chlorobenzoyl group into cis-like position (active)
6. 5-position on indole can contain e-withdrawing or e-donating groups

Question 21

Sulindac is Z or E isomer?

Answer 21

• Sulfoxide is in cis position with F group (Z-sulindac)
  o Z and E isomers (cis and trans isomer)
  o See which groups are the higher priorities and see which side they are on

Question 22

What is the metabolism of sulindac? (both inactivation and ativation)

Answer 22

Metabolism:

• Prodrug (sulfoxide) activated by CYP/FMO into sulfide group + inactivated by oxidation into sulfone

Question 23

How does Diclofenac cause hepatotoxicity?

Answer 23

Arylacetic acid + 2,6-dichloroanilino in ortho position
Activity:

• Anti-inflammatory, antipyretic, analgesic (better than indomethacin and aspirin)
• ADR: hepatotoxicity, (PO) GI issues since acidic
  o Major CYP3A4 metabolite (4-OH derivative) → can be metabolized into hepatotoxic quinonimine (C=O) → quinonimine can be inactivated by GSH → but when GSH is depleted, hepatocyte Cys residue can attack quinonimine forming an irreversible alkylation

Question 24

What is the significance of the 2 CL groups in diclofenac?

Answer 24

• -NH is a Bioisosteric replacement of -OH in salicylic acid
• 2-Chloro groups impt for activity→ they provide steric hindrance to C3-H & COOH → forcing a non-planar conformation between the rings → optimize binding

Question 25

Is nabumetone neutral/acidic/basic? Since nabumetone is a prodrug, what is the active metabolite and how is it produced?

Answer 25

Nature:

• Non-acidic prodrug –> does NOT induce direct GI mucosal damage

Chemical structure + metabolism:

• 1) C=O (ketone) can be reduced to OH by reductase , which then undergo glucuronidation
• 2) metabolised into 6-MNA (active) by beta-oxidase

Question 26

Which ibuprofen enantiomer is active?
Is ibuprofen neutral/acidic/basic?
What is the ADR of ibuprofen?

Answer 26

Chemical structure:

• 2-arylpropionic acid
• Chiral centre → S enantiomer is active
• Metabolized into many inactive metabolites → thus short duration of action
• R isomer is metabolised into S isomer (interconversion)
  Nature:
• Acidic (ADR: GI discomfort)

Question 27

What’s the difference btw COX-2i and COX-1i?
What is the effect of being COX-2 selective?

Answer 27

Chemical structure:
- Must be large so that they are selective for COX-2 –> by being rejected by COX-1 active site but still can bind to allosteric binding site which causes conformational change for enzyme inhibition

Nature + activity:
- Neutral + Selectivity for COX-2 **reduces damaging effects to gastric and intestinal mucosa **
- ADR: platelet aggregation, CVD damage

Question 28

What causes Gout attack?

Answer 28

Cause of Gout Attack:

• Xanthine oxidase converts hypoxanthine into xanthine → then oxidises into uric acid
• Uric acid is a weak acid (pKa5.7) → in physiological pH, it will deprotonate and become monoanion (50x more water soluble than uric acid)
• If uric acid rises too high, it can precipitate and crystalize in the joints and connective tissues → initiating gout attack

Question 29

Why does allopurinol have 50x greater affinity than hypoxanthine?

Answer 29

Allopurinol MOA + chemical structure:
- Xanthine mimic and competitive inhibitor of xanthine oxidase
- Pyrimidine ring is fused to a pyrazole instead of imidazole
- 50x higher affinity for xanthine oxidase than xanthine
- Thus uric acid levels will decrease