Statin drugs (NLU)

Báo cáo môn sinh dược học đại cương

NONG LAM UNIVERSITY HO CHI MINH CITY FACULTY OF BIOLOGICAL SCIENCES INTRODUCTION TO THE DISCOVERY PROCESS OF STATIN DRUG DEVELOPMENT Ho Chi Minh City, October 24, 2022 Presenter: Group Subjects: Sinh duoc hoc dai cuong Lecturers: Dr Le Van Huy MEMBERS LIST + WORK ASSIGNMENT GROU  Le Thanh Ai – 20126178 P      Do part Do part Huynh Tan An – 21126265 Do part Nguyen Hoai An – 21126267  Do part Nguyen Lan Anh – 21126009 Making powerpoint Nguyen Thi Lan Anh – Do the compilation, team 21126014 leader Do part  Tran Chau Anh – 21126900  Doan An Binh – 21126019 Do Ngoc Bao Chan – 10  11  21126287 Do part Tran Ngoc Bao Chau – Do part 21126288 Do part Vo Uyen Chi – 21126292 Do part Mai Nguyen Thuc Diem – 21126030 TOPIC OUTLINE Cholesterol and coronary heart disease Mechanism of action for statins pharmacodynamics Other targets for cholesterol lowering drugs Target enzyme Binding interactions of statins Effects of Statins The discovery of statins Other mechanisms of action for statins Statin’s achievements CHOLESTEROL AND CORONARY HEART DISEASE 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 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 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 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) 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 HMG-CoA 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 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 11 rosuvastatin 6 OTHER MECHANISMS OF ACTION FOR STATINS - 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 12 Other targets for cholesterol lowering drugs - Statins also are effective in reducing triglyceride levels in patients with hypertriglyceridemia 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 1030% by decreasing the absorption of bile acids in the intestine 13 EFFECTS OF STATINS - 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 14 + Reduce the risk of cardiovascular death + Reduce LDL levels effectively + Slow coronary atherosclerosis + Anti-oxidant stress effects 15 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 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 REFERENCES 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 Cholesterol có ý nghĩa sức khỏe tim mạch 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-cuaban/ 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-geneticdiseases/ 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 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 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/ 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/ 17 Stancu, C., & Sima, A (2001) Statins: mechanism of action and effects Journal of cellular and molecular 18