Enzymes As Drug Targets

Question 1

Enzyme inhibitor definition

Answer 1

Molecule that binds to an enzyme and decreases it activity.
Prevents substrate from entering enzymes active site and catalysing reaction

Question 2

Types of inhibition

Answer 2

Irreversible inhibitors - react with enzyme and change it chemically via covalent bond formation
Reversible inhibitors - bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex or both

Question 3

How do statins work as an inhibitor?

Answer 3

HMG-CoA reductase inhibitor
- Block the rate limiting step in the cholesterol pathway
- A class of lipid-lowering medication that reduce the level of bad cholesterol
- Primary prevention of CVD

Question 4

How do ACE-inhibitors work?

Answer 4

Work by inhibiting ACE thereby preventing the conversion of angiotensin I to Angiotensin II (Less AII to bind to Angiotensin receptors) = reduced vasoconstriction and thus hypertension as well as less aldosterone so less water and salt retained.

Question 5

How do NSAIDS work as an inhibitor?

Answer 5

They inhibit cyclooxygenase (COX) which is responsible for the breakdown of arachidonic acid to prostaglandin H2(PGH2) via competitive inhibition.
PGH2 usually produces prostanoids:
- PGD2 = mast cells
- PGE2 = vascular endothelial cells
- PG12 - platelets
- Thromboxane A2 = macrophages
NSAIDS prevent the production of the above

Question 6

What is different about Aspirin to other NSAIDS

Answer 6

Irreversibly blocks the active site of COX enzyme. Also, non-selective so acts on both COX-1 and COX-2

Question 7

What is the difference in COX-1 and COX-2

Answer 7

COX-1= found normally and widely around the body (normal physiology)
COX-2 = this is induced and found mainly in inflammation only

Question 8

Some enzymes can target multiple steps in biosynthetic pathways. What is a disease which requires treatment with a multiple enzymatic inhibitor drug

Answer 8

Parkinsons Disease
symptoms
- hypokinesia - decreased motor movement
- tremor at rest
- muscle rigidity, motor inertia
- cognitive impairment
- degenerative disease of basal ganglia
- early degeneration of dopaminergic neurons in the nigrostriatal pathway leading to autonomic dysfunction and dementia

Question 9

Difference between passive and active transport

Answer 9

Passive - symptom reduction (co-transporter protein) - Na/K/2Cl/NaCl
Active - ATP-ases - Na/K, K/H

Question 10

What are the different types of protein ports?

Answer 10

1. Uniports - use energy from ATP to pull molecules in
2. Symporters - use the movement in one molecule to pull in another molecule against a concentration gradient
3. Antiporters - one substrate moves against the gradient, using energy from the second substrate (mostly Na+, K+, or H+) moving down its gradient.

Question 11

Types of ion channels

Answer 11

Epithelial (sodium) - heart failure
Voltage gated (calcium, sodium) - nerve arrhythmia
Metabolic (potassium) diabetes
Receptors activated (chloride) - epilepsy

Question 12

Drug (xenobiotic) metabolism

Answer 12

The metabolic breakdown of drugs occurs through specialised enzymatic systems
The rate of metabolism determines the duration and intensity of a drugs pharmacologic action
Generate compounds that are more readily excreted (work in liver and kidney)
CYPs (e.g., cP540) are the major enzymes involved in drug metabolism (75%)
Most drugs undergo deactivation by CYP’s, either directly or by facilitated excretion from the body.
Also, many substances are bioactivated by CYPs to form their active compounds
CYPs metabolise thousands of endogenous and exogenous chemicals.