Chem 162/262 Final Exam Guide Spring 2009 (Kahn) The midterm exam in Chem 162/262 will test your knowledge and understanding of topics covered up to, and including the molecular recognition and sources of ligand and macromolecular structures for virtual screening. Docking will not be covered on the midterm. You can demonstrate your knowledge by answering specific questions (e.g. draw a double-reciprocal plot illustrative of competitive enzyme inhibition). You can demonstrate your understanding by explaining what approaches and techniques are best suited to solve a particular drug design problem (e.g. how would you develop a transition state analog for chorismate mutase). Of course, understanding a topic requires good knowledge of the material. You should have a good knowledge of different enzyme mechanisms covered in the course but you are not required to memorize specific drug structures, names, or mathematical formulas. An old sample exam key is available at http://www.chem.ucsb.edu/~kalju/chem162/private/Exam_162_Key.pdf 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) listening to old course audio, (ii) asking me or (iii) reading the textbook/literature/Internet. b) Textbook provides a nice coverage on enzymes, interactions, and lead modification principles. It provides some background on computer modeling. One of the strengths of the textbook is the good number of examples that are worked out in detail. I did not cover these examples explicitly but they are good illustrations of concepts that I talked. 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: the first two papers (Transition State Binding, The process of Structure-based drug design). Make sure that you know well the key messages from each paper. d) Tutorials and assignments that you have performed so far (excluding docking) Please review the midterm study guide for earlier topics. The new topics that I consider most important for the final are: 1. Mechanisms of enzyme action • Biological reasons for enzyme catalysis • Transition state stabilization concept • Acid-base catalysis • Covalent catalysis • Proximity and role of entropy in catalysis 2. Mechanistic classification of enzymes • Basis of classification of enzymes • Oxidoreductases, structure and function of NAD+ • Physiological role and chemical mechanism of IMP dehydrogenase • Oxidases, oxygenases, dioxygenases • Physiological role and mechanism of monoamine oxidase (see also textbook) • Transferases: • Physiological role and catalytic mechanism of catechol O-methyltransferase • Hydrolases: covalent and non-covalent mechanisms • Significance and mechanism of HIV protease • Lyases: significance and mechanism of orotidine monophosphate dehydrogenase • Isomerases: proline isomerase example • Ligases: gamma-carboxylase example • Databases of enzyme properties and mechanisms3. Molecular mechanism of additional enzyme targets that we discussed • Chorismate mutase • Thymidylate synthetase (see textbook) • DNA cytosine methyltransferase • Acetylcholinesterase • Hypoxanthine guanine phosphoribosyl transferase • Nucleoside N-hydrolase • Ketosteroid isomerase 4. Kinetics as a tool so study enzymes • What are kinetic studies good for • Practical aspects of kinetic measurements • Kinetic mechanisms • Enzyme inhibition models • Enzyme inactivation • Chemical versus product release step as a rate-limiting step • Use of the kinetic isotope effect to identify the rate-limiting step 5. Enzyme inhibition • Why to inhibit enzyme • Transition state analogs as inhibitors • Role of kinetic isotope effects in determining transition state structures • Design of IMP dehydrogenase inhibitors • Covalent inactivation of DNA methyltransferase 6. Intermolecular interactions • Interactions in the gas phase • Main contributors to interaction energy • Charge-charge and charge dipole interactions • Hydrogen bonding: cooperativity and secondary interactions • Charge-quadrupole interaction (Cation-π interaction) • Polarizability and van der Waals forces • Relationships between free energy, entropy, enthalpy, energy • Translational, rotational, vibrational entropy in binding • Structure of water and solvation of small molecules • Hydrophobic effect • Conformational entropy considerations in binding 7. Practical computational drug design • Visualization-based rational lead optimization • Building and minimization of molecular structures • Methods for optimization of transition state structures • Calculation and visual analysis of molecular electrostatic potential surfaces • Semiempirical, Hartree-Fock and Møller-Plesset methods intermolecular interactions 8. Structure-based drug design • Promises and problems of SBDD • The general process of SBDD • What can be computed about drugs • Quantum mechanics vs. molecular mechanics model • Semi-empirical vs. ab initio quantum mechanical model • Protein data bank as a source of macromolecular structures • Considerations for choosing macromolecular structures for SBDD • Promises and limitation of homology modeling • Commercial and free databases of available chemicals for virtual