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Lecture 1


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Lecture 1

  1. 1. International University of Africa Faculty of Pharmacy Medicinal Chemistry MCHM 311 Siddieg Omer Elsiddieg, M. Sc, B. Sc (Honors)
  2. 2. Class Policies and Rules <ul><li>Language of Instruction </li></ul><ul><li>Attendance Policy </li></ul><ul><li>In-Class Conduct </li></ul><ul><li>Class Materials </li></ul><ul><li>Office Hours </li></ul><ul><li>Laboratory, Homework, Assignments, and Term Paper </li></ul><ul><li>Exams and Grading Policy </li></ul><ul><li>Academic Integrity </li></ul>
  3. 3. Class Contents <ul><li>Introduction to Medicinal Chemistry </li></ul><ul><li>Physicochemical Properties of Drugs in Relation to Biological Activities </li></ul><ul><li>Receptors: Structures and Functions </li></ul><ul><li>Principles of Drug Design </li></ul><ul><li>Drug Metabolism </li></ul><ul><li>Factors Influencing Drug Metabolism </li></ul><ul><li>Toxic Effects of Drug Metabolism </li></ul>
  4. 4. What Is Medicinal Chemistry?
  5. 5. <ul><li>“ A chemistry-based discipline, involving aspects of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification, and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure activity relationships (SARs), the relationship between chemical structure and pharmacological activity for a series of compounds.” </li></ul>
  6. 6. <ul><li>“ is the applied science that is focused on the design (or discovery) of new chemical entities (NCEs) and their optimization and development as useful drug molecules for the treatment of disease processes”. </li></ul>
  7. 7. <ul><li>In achieving this mandate, the medicinal chemist must: </li></ul><ul><li>Design and synthesize new molecules. </li></ul><ul><li>Ascertain how they interact with biological macromolecules (such as proteins or nucleic acids). </li></ul><ul><li>Elucidate the relationship between their structure and biological activities. </li></ul><ul><li>Determine their absorption and distribution throughout the body. </li></ul><ul><li>Evaluate their metabolic transformations. </li></ul>
  8. 8. <ul><li>Medicinal Chemistry is Interdisciplinary: </li></ul><ul><li>Theoretical Chemistry </li></ul><ul><li>Organic Chemistry </li></ul><ul><li>Analytical Chemistry </li></ul><ul><li>Molecular Biology </li></ul><ul><li>Pharmacology </li></ul><ul><li>Biochemistry </li></ul><ul><li>Bottom Line: </li></ul><ul><li>Design and synthesis of new drugs </li></ul>
  9. 9. <ul><li>How Did we Arrive Here? </li></ul><ul><li>A brief History of Medicinal Chemistry </li></ul><ul><li>Ideas, tools, and knowledge that advanced contemporary medicinal chemistry </li></ul>
  10. 10. Drugs of Antiquity <ul><li>Fats, Oils, honey, wax and milk were used </li></ul><ul><li>Mud, and Salts were used for wound dressing </li></ul><ul><li>Fried Ox Liver for blidness </li></ul>
  11. 11. The Middle Ages <ul><li>The use of Antimony salts as alixirs </li></ul>
  12. 12. The Nineteenth Century <ul><li>Expansion of chemical knowledge </li></ul><ul><li>Focus on finding the active ingredients in the plants and animal remedies (e.g. isolation of morphine). </li></ul><ul><li>Increased use of pure substances </li></ul><ul><li>Birth of pharmaceutical industry </li></ul>
  13. 13. The twentieth Century <ul><li>Domagk discovery of sulfa drugs (Prontosil) </li></ul><ul><li>Discovery of penicillin </li></ul><ul><li>Modern medicinal chemistry </li></ul>
  14. 15. <ul><li>What are Drugs? </li></ul>
  15. 16. <ul><li>A drug molecule possesses one or more functional groups positioned in three-dimensional space on a structural framework that holds the functional groups in a defined geometrical array that enables the molecule to bind specifically to a targeted biological macromolecule, the receptor . </li></ul>
  16. 17. <ul><li>The structure of the drug molecule thus permits </li></ul><ul><li>a desired biological response, which should be beneficial (by inhibiting pathological processes) and which ideally precludes binding to other untargeted receptors, thereby minimizing the probability of toxicity. </li></ul>
  17. 18. <ul><li>The framework upon which the functional groups are displayed is typically a hydrocarbon structure (e.g., aromatic ring, alkyl chain) and is usually chemically inert so that it does not participate in the binding process. The structural framework should also be relatively rigid (“conformationally constrained”) to ensure that the array of functional groups is not flexible in its geometry, thus preventing the drug from interacting with untargeted receptors by altering its </li></ul><ul><li>molecular shape </li></ul>
  18. 19. <ul><li>To be successful in countering a disease process, however, a drug molecule must have additional properties beyond the capacity to bind to a defined receptor site. </li></ul><ul><li>It must be able to withstand the journey from its point of administration (i.e., the mouth for an orally administered drug) until it finally reaches the receptor site deep within the organism (i.e., the brain for a neurologically active drug) </li></ul>
  19. 20. <ul><li>Receptor macromolecules are frequently proteins or glycoproteins. Certain properties must be present if a macromolecule is going to have what it takes to be a druggable target. The receptor macromolecule must be intimately connected with the disease in question, but not integral to the normal biochemistry of a wide range of processes. </li></ul>
  20. 21. <ul><li>A drug is most effective when its structure or a significant part of its structure, both as regards molecular shape and electron distribution (stereoelectronic structure), is complementary with the stereoelectronic structure of the receptor responsible for the desired biological action. </li></ul><ul><li>The section of the structure of a ligand that binds to a receptor is known as its pharmacophore. </li></ul>
  21. 22. Drug Discovery and Design <ul><li>Know what properties turn a molecule into a drug </li></ul><ul><li>Know what properties turn a macromolecule into a drug receptor. </li></ul><ul><li>Know how to design and synthesize a drug to fit into a receptor </li></ul>
  22. 24. Lead Compounds <ul><li>What are the lead compounds? </li></ul><ul><li>Promising starting compounds </li></ul><ul><li>How to identify them? </li></ul><ul><li>Rational drug design </li></ul><ul><li>Random high throughput screening, </li></ul><ul><li>Focused library screening </li></ul><ul><li>How to optimize them? </li></ul><ul><li>QSAR studies </li></ul>
  23. 25. Sources of Drugs and Lead Compounds <ul><li>Natural Sources : </li></ul><ul><li>Are still important sources of lead compounds and new drugs. </li></ul><ul><li>The large diversity of potential natural sources in the world makes the technique of random screening a rather hit or miss process. </li></ul><ul><li>Eethnopharmacology offers the basis of a more systematic approach. </li></ul>
  24. 27. <ul><li>Identifying a material containing an active compound: </li></ul><ul><li>Extraction </li></ul><ul><li>Purification </li></ul><ul><li>Assessment of the pharmacological activity </li></ul>
  25. 28. <ul><li>The isolation of useful quantities of a drug from its land or sea sources can cause ecological </li></ul><ul><li>problems. </li></ul>
  26. 30. Yew Tree
  27. 31. Drug Synthesis <ul><li>Start with the pathology of the diseased state and determine the point where intervention is most likely to be effective. </li></ul><ul><li>Lead compounds are then synthesized and their pharmacological activity evaluated. </li></ul><ul><li>Analogues are produced and screened. </li></ul><ul><li>Labor intensive </li></ul>
  28. 33. Me-Too Drugs <ul><li>A way to cut the cost of producing drugs </li></ul><ul><li>By synthesizing and marketing drugs that are similar in structure and activity to those produced by competitors. </li></ul>
  29. 34. Classification of Drugs <ul><li>Drugs are classified in a number of different ways depending on where and how the drugs are being used. </li></ul><ul><li>Chemical structures </li></ul><ul><li>Pharmacological Action (site of action, targeted system). </li></ul>
  30. 35. <ul><li>Drugs with similar chemical structures may have different pharmacological activities. </li></ul>
  31. 37. Routes of Administration
  32. 38. Pharmacokinetics Phase <ul><li>The pharmacokinetic phase of drug action includes the Absorption, Distribution, Metabolism and Elimination (ADME) of the drug. </li></ul>
  33. 39. Absorption <ul><li>Absorption is the passage of the drug from its site of administration into the plasma after enteral administration. </li></ul><ul><li>It involves the passage of the drug through the appropriate membranes. </li></ul>
  34. 40. <ul><li>Good absorbance requires that a drug molecule has the correct balance between its polar (hydrophilic) and </li></ul><ul><li>nonpolar (hydrophobic) groups. </li></ul><ul><li>Drugs that are too polar will tend to remain in </li></ul><ul><li>the bloodstream, whilst those that are too nonpolar will tend to be absorbed into and remain within the lipid interior of the membranes. </li></ul>
  35. 41. Distribution <ul><li>Distribution is the transport of the drug from its initial point of administration or absorption to its site of action. </li></ul><ul><li>The main route is the circulatory system; however, some distribution does occur via the lymphatic system. </li></ul>
  36. 42. Metabolism <ul><li>Drug metabolism is the biotransformation of the drug into other compounds referred to as metabolites. </li></ul><ul><li>These biotransformations occur mainly in the liver </li></ul><ul><li>but they can also occur in blood and other organs such as the brain, lungs and kidneys. </li></ul>
  37. 44. Elimination <ul><li>Elimination is the collective term used for metabolic and excretion processes that irreversibly remove a drug from the body during its journey to its site of action. It reduces the medical effect of the drug by reducing its concentration at its site of action. </li></ul><ul><li>Slow Elimination </li></ul><ul><li>Rapid Elimination </li></ul>
  38. 45. Bioavailability of Drugs <ul><li>The bioavailability of a drug is defined as the fraction of the dose of a drug that is found in general circulation It is influenced by such factors as ADME. </li></ul><ul><li>Bioavailability is not constant but varies with the body’s physiological condition. </li></ul>
  39. 46. Pharmacodynamic Phase <ul><li>Pharmacodynamics is concerned with the result of the interaction of drug and body at its site of action, that is, what the drug does to the body. </li></ul><ul><li>A drug is most effective when its shape and electron distribution, that is, its stereoelectronic structure, is complementary to the steroelectronic structure of the active site or receptor. </li></ul>
  40. 47. <ul><li>THE END </li></ul>