Chem 162/262 Exam Guide Winter 2008 (Kahn) The exam takes 50 minutes. The exam will test your knowledge and your understanding of the material that was covered in the lectures, tutorials, and in the required literature. You can demonstrate your knowledge by answering specific questions (e.g. draw a graph illustrating the expected results from displacement assay in the absence of cooperativity). You can demonstrate your understanding by explaining what approaches and techniques are best suited to solve a particular drug design problem (e.g. how could you design a molecule that would inhibit a novel mutant form of influenza neuraminidase). Of course, understanding a topic requires good knowledge of the material. However, you are not required to memorize specific drug structures, names or mathematical formulas. In general, my exams tend to be of problem-solving type. You may want to check out sample questions with answers from a previous exam. I believe that the following resources help you best in preparing for the exam: a) Lecture material. Was there anything that I said and was not clear? If so, please see if you can get answers by (i) discussing the topic with fellow students, (ii) asking me, or (iii) reading the textbook/literature/Internet. b) Textbook provides a nice coverage on enzymes, receptors, and lead modification principles. It provides some background on computer modeling. One of the strengths of the textbook is the number of examples that are worked out in great detail. I covered few of these examples explicitly but there are several others that I left alone. The textbook also has a good number of end-of-chapter practice problems. I like some of them so much that I consider adopting them for the exam. c) Required reading. I did not post as much as usually this year and thus I expect that you know it all. First, make sure that you have some idea what is the main point of each of these papers. Then see if which papers you need to read more thoroughly to strengthen your understanding of the material. You are not expected to know topics from Chem162A but a review of principles of enzymes and biocatalysis is recommended. The topics that I consider most important for the final are: 1. Biological role and function of receptors • General properties of receptors and signal transduction • Structure of biological membranes (review your Chem 142A material) • Classification of receptors • Structure and function of nicotinic acetylcholine receptor • Structure and function of ionotropic glutamate receptors • Structure and function of GPCRs • Structure and function of tyrosine kinase-linked receptors • Structure and function of estrogen receptor and thyroid hormone receptor 2. Membrane receptor studies • The concept of agonists and antagonists; design strategies • Why to design ligands for membrane receptors • Binding studies: practical considerations • Displacement assays: principles • Prediction of receptor structures 3. Assay development for receptors • How to develop an assay: general considerations • Biochemical assays: binding isotherm, displacement assay • Cell-based assay and whole animal models for disease • Specific assays for GPCRs4. Ligand-based design • Principles of agonist and antagonist design, nicotinic receptor ligands • Pharmacophore, methods for its identification • Common reasons to modify leads • Structure-activity studies • Classical approaches to structure modification • Specific examples we covered: epibatidine analogs, cimetidine, opioids (see textbook for details) • Chemical informatics: SMILES, databases, SDF files • Fragment-based design 5. Theoretical background for ligand-based design • Computational methods for ligand-based design (including paper by Bill Jorgensen) • Principles and practice of conformational analysis 6. Intermolecular interactions • Interactions in the gas phase • Charge-charge and charge dipole interactions • Polarizability and van der Waals forces • Relationships between free energy, entropy, enthalpy, energy • Enhtalpically and entropically favorable drugs (HIV protease inhibitors paper) • Hydrophobic effect • Conformational entropy considerations in binding 7. Semi-quantitative structure-based drug design • Promises and problems of SBDD • The general process of SBDD • Importance of high-resolution target structures • Visualization-based rational lead optimization • What can be computed about drug targets • Protein electrostatic potential maps in drug design • Docking as lead discovery / optimization approach • Specific steps for docking with the program DOCK • Importance of receptor flexibility in docking • Literature examples of structure-based drug design (e.g. nicotinic acetylcholine receptor, protein kinase inhibitors, HIV protease) 8. Quantitative structure-based drug design • The concept of statistical ensembles • The concept of partition function and its relation to free energies • Molecular dynamics and Monte Carlo as methods of statistical sampling • Implicit vs. explicit solvent models 9. Drug metabolism and prodrugs • Basic pharmacokinetics, sites of drug metabolism, liver and first pass effect • Common phase I reactions and their effect on drug solubility / toxicity • Common phase II reactions and their effect on drug solubility / toxicity • Structure and mechanism of P450 enzymes • Design strategies that consider metabolism • Examples illustrating the complexity behind drug toxicity (incl. COX-2 inhibitors) • Common reasons and approaches to prodrug design • Literature examples of successful prodrug design