(Dr Aisyah’s part, 2018/1)
Learning outcomes for this course.
By the end of the course, you should be able to:
CO1: describe the overall process of drug discovery and development (hits-to-market) by explaining the roles and the state of the art tools that are being employed by medicinal chemists at each stage of this process.
CO2: apply the knowledge of drug discovery and development process by linking the structure, physical and chemical properties of drugs to simulated scenarios and biological processes.
Weekly lesson outcomes
In order to do well in the Exam (and hopefully later as Pharmacists), you should be able to do the following:
1. Describe the overall process of “drug to market” , the role of chemistry in the various phases of drug activity– pharmaceutics: formulation, disintegration and dissolution, pharmacokinetics and pharmacodynamic (drug-receptor interactions).
2. Sketch how drugs are discovered and developed (brief history of drug discovery). Distinguish the expression of drug effects, and explain in your own words the terms (e.g. agonist, antagonists).
3. Describe how SAR study is performed on natural products with high therapeutic potential (the reductionist approach); but why natural products need SAR study?
4. Given a drug or its derivatives, identify the appropriate forces of interactions of functional group and a receptor/enzyme. For example, sketch the potential interactions between a drug-receptor e.g. ionic, covalent, non-polar interactions (hydrogen bond acceptors and donors (HBA and HBD), weak interactions (e.g. van der Waals, pi-pi, pi-ionic interactions).
>>> Remember in SAR (pharmacodynamics) it’s about interactions. Few drugs would elicit reactions.
5. Given a sketch of molecule-enzyme, draw the appropriate binding interactions between functional groups on the molecule with the amino acids on the enzyme, e.g. salt-bridges, binding interactions (e.g. aromatic groups on drug with Tyr). Use appropriate chemical drawing conventions for binding interactions (e.g. a solid line for covalent bonds, a dotted/hash line for weak bonds).
6. Sketch and describe key discoveries and/or optimisation strategies in the development of a drug in question. ACE inhibitors (e.g. captopril, enalapril), adrenergic receptor inhibitors (e.g. propanolol, salbutamol), aspirin. For example, explain why enalaprilat is formulated as a prodrug? What type of prodrug is selected for enalaprilat? How was atenolol discovered? Describe how adrenergic receptor inhibitors are designed for selectivity?
>>> Use a diagram, a flowchart to illustrate the key discoveries and optimisation strategies used in these drug examples. Check out my video on ACE Inhibitors for revisions.
7. Explain factors affecting binding interactions between drug-receptor and their characteristics (e.g. factors influencing hydrogen bonding interactions). Describe how would you study a binding interaction between a drug and a receptor (e.g. if hydrogen bond is thought important, which functional group can be modified to study this interaction and explain why).
8. List strategies in drug optimisation. Outline and discuss optimisation strategies of drug in SAR (how to study drug-receptor interactions and improve the interactions) in research and pharmaceutical industries. Outline the importance of stereochemistry in drugs and how it affects drug-receptor interactions. Use appropriate drug examples to discuss the strategies in drug optimisation.
9. Describe the general factors influencing ADME of a drug. Recall by describing key biotranformation reactions with its enzymes and toxicity-associated metabolites/metabolisms.
10. Distinguish key transporters and relevant absorption mechanisms involved for most drugs (hydrophobic or polar in nature).
11. Use the classic Henderson-Hasselbalch (HH) equation for absorption to calculate the extent of drug ionisation (as ratio, % and in grams) after its disintegration and dissolution in the different parts of GIT (Acid-base concepts).
12. Describe and apply Lipinski’s Rule of 5 (Ro5) to evaluate the potential of a molecule as an oral drug. Explain the extent of Lipinski’s Ro5 in relation to drug absorption (see 10, 11). Explain the limitations of Ro5. Suggest other considerations.
13. Given a drug, use clogP and Lemke’s Empiric formula to calculate and predict drug solubility from a given set of data on water solubilising potential of functional groups and hydrophilic-lipophilic values for organic fragments. A table of Lemke’s solubilising potential and hydrophilic-hydrophobic substituent constants of functional groups will be given as Appendix in the exam. So no need to memorise them.
14. Explain and compare/contrast approaches and modifications to optimise delivery of drugs to targets via prodrug and bioprecursor design (general) and macromolecular carriers for drug targeting.
15. Briefly explain chemical modifications (e.g. bioisosteres, salts (soluble/insoluble), cyclodextrin, solubilising functionalities) of drugs as a way to solve problems associated with pharmaceuticals (e.g. to alter/improve tastes, pH, solubility, patient compliance, painful injection, toxicity, delivery of drugs).
16. Describe the key differences and similarities between chemical names, trade names and international nonproprietary (INN) drug names and its uses. Why INN? Why brand names? And why not? Explain.
17. Explain drug nomenclature (Who, What, Why, How, Where) and describe the ATC classification.
18. Define and identify”stems” in drugs and biopharmaceuticals and its uses. For no. 9-18, please go through these thinglinks on 1-minute videos and lecture notes available.
All the best guys!!
This ‘Study Guide for Medicinal Chemistry FAR212’ is licensed under CC BY-NC-ND
by Dr Aisyah Saad, 2018 unless stated otherwise.