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Mid-term Exercises E8130 – Medicinal Chemistry SOLUTIONS 1) Name three intramolecular attractive forces that contribute to a productive drug-target interaction and provide for each of them one typical functional group and/or specific amino acid that can engage in this type of binding. a) van-der Waals interaction typical functional group: phenylalanine (also correct: Val, Leu, Trp, Ile,... b) H-bonding interaction typical functional group: peptidic amide bond (also correct: Ser, Thr, Tyr,...) c) halogen-bonding typical functional group: histidine another possibility: d) ionic bonding typical functional group: arginine (also correct: Lys, Asp, Glu) 2) The first pass effect plays a crucial role in the activation and/or deactivation of drugs. Briefly describe the general features of the first pass and explain its particular function in the activation of the following two prodrugs (involved enzymes, structure of the generated active form). O O O O Me2N Cl clofibrate (LDL lowering agent) tamoxifen (anti-estrogen) (the important terms are marked bold) The first pass describes the effect, that orally administered drugs are absorbed in the gastrointestinal system (stomach and/or small intestines) from where they pass the liver via the portal vein before reaching the systemic blood stream and the target organs. The liver provides a very effective enzymatic machinery with highly active hydrolases, oxygenases and reductases. Drugs are thereby structurally altered which can lead to deactivation, activation or the formation of toxic metabolites. The prodrug concept exploits the first pass by using molecules that do not act as drug, but that can be activated by cleavage of labile groups or oxidation to yield the bioactive compound. Prodrugs often show better membrane permeability and are hence easier absorbed. Prodrug concept in clofibrate: ester hydrolysis O O O esterase O O Cl OH Cl Prodrug concept in tamoxifen: hydroxylation O Me2N cytochrome P450 O Me2N OH 3) Indicate one potential pharmaceutical application for each of the following drug molecules. What are the target proteins of the drugs (if applicable) and which physiological function is modulated by the interaction. a) b) OH OH O COOH N OH O F OH c) H H H H O a) application: cholesterol-lowering agent, prevention of stroke or cardiac arrest (one is enough) target protein: HMG-CoA reductase modulated function: biosynthesis of cholesterol (also ok: mevalonate, terpene bio synthesis) b) application: pain killer, antiinflammatory agent, anti-coagulant (one is enough) target: cyclooxygenase modulated function: prostaglandin/thromboxane biosynthesis c) application: against growth failure diseases, bone marrow stimulation, muscle growth (one is enough) target: androgen receptor modulated function: signaling cascade to develop male sexual characteristics, ...to support gain of bone structure and sceletal muscles 4) Briefly explain the function of low-density lipoproteins and its involvement in plaque formation. (the important terms are marked bold) Low-density lipoprotein (LDL) is a transport vesicle for lipophilic compounds such as triglycerides and cholesterol. It transports cholesterol from the liver to the target tissues and serves as reservoir for cholesterol in the blood. LDL is instable and readily associates with the arterial walls. Accumulation of LDL leads to the formation of foam cells/fatty streak which eventually results in thrombotic clot formation.