Statin drugs (NLU)

Báo cáo môn sinh dược học đại cương

INTRODUCTION TO THE DISCOVERY PROCESS OF STATIN DRUG DEVELOPMENT

NONG LAM UNIVERSITY HO CHI MINH CITY

FACULTY OF BIOLOGICAL SCIENCES

Lecturers: Dr Le Van Huy

Presenter: Group 1

Ho Chi Minh City, October 24, 2022

Subjects: Sinh duoc hoc dai cuong

 Le Thanh Ai – 20126178

21126014

21126287

21126288

21126030

GROU

P 1

2

MEMBERS LIST + WORK ASSIGNMENT

Do part 7

Making powerpoint

Do the compilation, team leader

Do part 4

Do part 3

Do part 8

Do part 1

Do part 9

Do part 6

Do part 2

Do part 5

1 2 3 4

5 6

7 8 9

10 11

TOPIC OUTLINE

1 Cholesterol and

coronary heart disease 2 Target enzyme

3 The discovery of

statins

4 Mechanism of action for statins - pharmacodynamics

5 Binding interactions of statins

6 Other mechanisms

of action for statins

7 Other targets for

cholesterol lowering

drugs

9 Statin’s achievements

8 Effects of Statins

1 CHOLESTEROL AND CORONARY HEART DISEASE

4

What is Cholesterol?

- Cholesterol is a component of blood lipids and plays an important role in most body activities

- Cholesterol is formed from two sources, either synthetically or from food, produced in the liver and from animals such as meat, milk, egg yolks, and animal viscera

2 TARGET ENZYME

Target enzyme

- Enzymes are attractive targets for pharmacological intervention, owing to their essential roles in life processes and pathophysiology

- Enzyme Targeting: Over the last few years, diseases caused by dysfunctional

or missing enzymes have been treated with a type of therapy called enzyme replacement therapy or ERT

6

3 THE DISCOVERY OF STATINS

- Statin drug group is one of the best lipid control drugs and is also used in preventing cardiovascular events

- HMG-COA Reductase inhibitors, are a key drug used to treat blood lipoprotein disorders and prevent cardiovascular events

- Cholesterol is essential for the functioning of all human organs, but it is nevertheless the cause of coronary heart disease

- The statins that lower cholesterol levels in the blood and reduce the frequency of heart attacks

3 THE DISCOVERY OF STATINS

STATIN

- Statins are the drug that help lower cholesterol levels in the blood

- Statins help prevent coronary heart disease in patients without a history of CVD (primary prevention)

8

Pharmacological Action

- Statin is a competitive inhibitor of HMG-CoA reductase which catalyzes the rate-limiting step

- Inhibition of the enzyme decreases de-novo cholesterol synthesis, increases expression of LDL receptors

- Also reduces blood level of triglycerides and slightly increases level of HDL

4 MECHANISM OF ACTION FOR STATINS - PHARMACODYNAMICS

- The statins work by acting as competitive inhibitors Both the polar head group and the hydrophobic moieties are important to the action of statins All the statins share the same polar head group and it is this group that mimics the natural substrate (HMG-CoA)

- Hydroxymethylglutaryl-CoA (HMG-CoA) reductase which is the enzyme responsible for converting HMG-CoA to mevalonate in the cholesterol synthesis pathway

5 BINDING INTERACTIONS OF STATINS

- The binding interactions of the substrate with the enzyme have been studied

by X-ray crystallography

- The polar head group of the statins binds to the enzyme reflecting the marked flexibility that is inherent to the enzyme

10

5 BINDING INTERACTIONS OF STATINS

How the substrate binds to HMGR:

- A statin binds, and the enzyme alters its shape differently The movement of flexible C-terminal alpha helices exposes a shallow, but different,

hydrophobic binding region next to the active site that can accommodate the hydrophobic moiety present in the statin

- Atorvastatin and rosuvastatin can form an extra hydrogen bonding interaction with the enzyme that does not occur with other statins

- The serine residue which acts as a hydrogen bond donor to the carbonyl oxygen atom of atorvastatin ( Fig CS1.12 ) or the sulphone oxygen of

6 OTHER MECHANISMS OF ACTION FOR STATINS

12

- The action of statins is not purely down to inhibition of HMGR

- The beneficial effects of statins are the result of their capacity to reduce cholesterol biosynthesis, mainly in the liver Statins have antiatherosclerotic effects Statins reduce significantly the incidence of coronary events Statins interfere with events involved in bone formation and impede tumor cell growth

7 Other targets for cholesterol lowering drugs

- Statins also are effective in reducing triglyceride levels in patients with hyper-triglyceridemia The major side effects are muscle complications and an increased risk of diabetes The different statins have varying drug interactions:

+ Ezetimibe lowers LDL-C levels by approximately 20% by inhibiting cholesterol absorption by the intestines leading Bile acid sequestrants lower LDL-C by 10- 30% by decreasing the absorption of bile acids in the intestine

8 EFFECTS OF STATINS

14

- Statin drugs are acting by cholesterol synthesis in the liver, thus reducing total cholesterol levels:

+ Preventing HMG - CoA into Mevalonate, can reduce cholesterol levels in plasma + Inhibit atherosclerosis by reducing the formation of Superoxide and other

oxygen roots that turn many intracellular signal pathways + Stable effect on atherosclerotic plaques by inhibiting MMP-9 secretion + Reduce the risk of cardiovascular death + Reduce LDL levels effectively + Slow coronary atherosclerosis + Anti-oxidant stress effects

9 STATIN’S ACHIEVEMENTS

According to the Alzheimer Association, a recent evaluation of data from 11 studies including more than 23,000 people showed that statin users from 3 to

25 years reduced 29% of the risk of developing intellectual decline These studies support other studies showing that people with high cholesterol in the middle-aged period are at higher risk of dementia

16

1 Collins, R., Reith, C., Emberson, J., Armitage, J., Baigent, C., Blackwell, L., Blumenthal, R., Danesh, J., Smith, G D., DeMets, D., Evans, S., Law, M., MacMahon, S., Martin, S., Neal, B., Poulter, N., Preiss, D., Ridker, P., Roberts, I., Rodgers, A., … Peto, R (2016) Interpretation of the evidence for the efficacy and safety of statin therapy Lancet (London, England), 388(10059), 2532–2561 https://doi.org/10.1016/S0140-6736(16)31357-5

2 Cholesterol có ý nghĩa gì đối với sức khỏe tim mạch của bạn? | Vinmec (n.d.) Retrieved October 6, 2022,

from Bệnh viện Đa khoa Quốc tế Vinmec | Vinmec website:

https://vinmec.com/vi/tim-mach/thong-tin-suc-khoe/cholesterol-co-y-nghia-gi-doi-voi-suc-khoe-tim-mach-cua-ban/

3 Ahmed, R (2021, December 16) Are Enzymes Good Therapeutic Targets for treating rare genetic diseases?

Retrieved October 6, 2022, from Perspectives from Gain Therapeutics website:

https://perspectives.gaintherapeutics.com/are-enzymes-good-therapeutic-targets-for-treating-rare-genetic-diseases/

4 Enzyme Target and Screening - Creative BioMart (n.d.) Retrieved October 6, 2022, from Creative BioMart -

Recombinant Protein, Native Protein, GMP Protein And Cell Lines - Creative BioMart website:

https://www.creativebiomart.net/Enzyme-Target-and-Inhibitor-Screening.htm

5 Saxena, M., & Dubey, R (2019) Target Enzyme in Alzheimer's Disease: Acetylcholinesterase Inhibitors Current topics in medicinal chemistry, 19(4), 264–275 https://doi.org/10.2174/1568026619666190128125912

6 Sizar O, Khare S, Jamil RT, et al Statin Medications [Updated 2022 May 1] In: StatPearls [Internet] Treasure Island (FL): StatPearls Publishing; 2022 Jan- Available from: https://www.ncbi.nlm.nih.gov/books/NBK430940/

7 Department of Chemistry - The University of Manchester (n.d.) Retrieved October 6, 2022, from Department

of Chemistry - The University of Manchester website: http://www.chemistry.manchester.ac.uk/

8 Stancu, C., & Sima, A (2001) Statins: mechanism of action and effects Journal of cellular and molecular

medicine, 5(4), 378–387 https://doi.org/10.1111/j.1582-4934.2001.tb00172.x

REFERENCES

17