(16:663:502) Instructors: Longqin Hu and John Kerrigan Direct questions and enquiries to the Course Coordinator: Longqin Hu For more current information, please check WebCT at https://webct.rutgers.edu Tentative Course Outline I. Introduction to The Drug Discovery/Development (Hu) 2 lecture BMC Chp 2 p1-36 and Chp 9 p251-300 A. Drug Discovery 1. Definition of Drug Discovery 2. Stages of drug discovery 3. Strategic Issues in drug discovery B.. Drug Development 1. Chemistry 2. Preclinical Studies 3. Transition from Preclinical to Clinical 4. Planning the Drug Development Process 5. Clinical Research C.. Source of Drugs 1. Drugs from Natural Sources (Natural Products) a. Plants b. Animals c. Microorganisms (Fungi, Bacteria) 2. Drugs from Organic Synthesis D. Structural effects on drug action 1. Sequence of events after drug administration 2. Physico-chemical properties that are related to drug action 3. Structurally Non-Specific Drugs 4. Structurally Specific Drugs 5. Role and types of chemical bonding involved in drug-target interactions 6. Steric factors and pharmacological activity E.. The Gleavec Story: discovery and development (Dr. Ray Baktiar, Merck Research Lab)
Course Outline Page 2 II. Approaches to New Drug Discovery (Hu) 2 lectures BMC Chp 19 p783-802 MCPP Chp 13-14 p189-225 A. Drugs Derived from Natural Products B. Existing Drugs as a Source for New Drug Discovery C. Using Disease Models as Screens for New Drug Leads D. Physiological Mechanisms: the Modern Rational Approach to Drug Design E: Approaches to Lead Optimization 1. Bioisosteric replacement 2. Conformation restriction a. Increase selectivity b. Increase affinity 3. Pharmacophore 4. Molecular dissection 5. Metabolic stabilization III. Enzymes as Targets of Drug Design (Hu) 7 lectures BMC Chp 18 p733-782 A. Enzyme kinetics (Hu) 1. The Michaelis-Mention Equation 2. Steady state of an enzyme-catalyzed reaction 3. Validity of the Steady-state assumption 4. Graphs of the Michaelis-Mention Equation 5. Practical aspects of kinetic studies B. Enzyme inhibition and activation (Hu) 1. Reversible and irreversible inhibition 2. Linear inhibition 3. Plotting inhibition results 4. Inhibition by a competing substrate 5. Enzyme activation C. Approaches to the Rational Design of Enzyme Inhibitors (Hu) 1. Transition state analogues 2. Mechanism-based inhibitors 3. Affinity labels D. Farnesyl transferase inhibitors: Design and Synthesis (Dr. Theresa Williams, Merck Research Laboratory, West Point) E. Structure-based design of thrombin inhibitors (Dr. David Kimball, Lexicon Pharmaceuticals) 1. Coagulation cascade 2. Structure of enzyme 3. Structure of enzyme inhibitor complexes 4. Medicinal chemistry 5. The challenges of pharmacokinetics
Course Outline Page 3 F. Selective inhibitors of cyclin-dependent kinases (Dr. David Kimball) 1. Kinases 2. Is selective inhibition possible with ATP mimetics? 3. Medicinal chemistry 4. Challenges in vivo IV. Receptors as Targets of Drug Design (Hu) 2 lectures BMC Chp 11 p349-397 A. Receptor Theory B. Receptor Complexes and Allosteric Modulators C. Second and Third Messenger Systems D. Molecular Biology of Receptors F. Receptor Models and Nomenclature G. Receptor Binding Assays H. Lead Compound Discovery of Receptor agonists and antagonists 1. Natural Product Sources 2. Pharmacophore-based Ligand Libraries 3. Diversity-based ligand libraries 4. High-throughput screening V. Computer-Aided Drug Design (Kerrigan) 10 lectures A. Molecular Mechanics Force Fields 1. Introduction 2. MM2/MM3/MM4 force fields 3. CFF93 force field 4. AMBER 5. CHARMM (BIO+) 6. OPLS 7. ECEPP 8. The Merck force field (MMFF94) 9. Advantages and Disadvantages of the force field methods B. Solvation Effects in Molecular Mechanics 1. Introduction 2. Molecular solvent models 3. Continuum solvent models a. Surface area based b. Poisson-Boltzmann c. The GB/SA continuum model 4. Model comparison C. Minimization techniques 1. Simplex method
Course Outline Page 4 2. Line searching 3. Steepest descent 4. Conjugate gradient 5. Full matrix Newton-Raphson 6. Block diagonal Newton Raphson 7. Saddle Point search 8. Cerjan-Miller algorithm D. Conformational Analysis 1. Grid Search 2. Monte Carlo 3. Global minimum search 4. Macrocycles 5. Complexes & docking 6. Symmetry E. Binding Free Energy Calculation 1. Direct calculation 2. Calculation of Interaction Energies (Halgren s Method) 3. Multidimensional Monte Carlo integration F. Case Study(ies)/Applications 1. Conformational Analysis of substrate-macromolecule complexes 2. Deriving and using 3-dimensional pharmacophores 3. Structure-based methods to identify new lead compounds 4. De novo ligand design 5. Molecular similarity 6. QSAR VI. Combinatorial Chemistry (Sun) 4 lectures CC Chp 3. p51-97 Chp 7. p177-198 Chp 14. p399-411 A. Introduction: Concepts and Terms B. Solid-phase Strategies 1. General Strategies and Concepts 2. Specific Implementation Issues a. Solid support b. Anchoring chemistry c. Coupling chemistry d. Protection schemes e. Analytical methods C. Solution Phase Strategies D. High Throughput Screening
Course Outline Page 5 Reference Textbooks: BMC Burger s Medicinal Chemistry and Drug Discovery, 5th Edition, Vol. 1. Principles and Practice, edited by M. E. Wolff, John Wiley & Sons: New York, 1995. PMC Principles of Medicinal Chemistry, 4th Edition, edited by W.O. Foye, T.L. Lemke, and D. A. Williams, Williams and Wilkins: Philadelphia, 1995. MCPP Medicinal Chemistry: Principles and Practice, edited by F.D. King, Royal Society of Chemistry: Cambridge, 1994. CC A Practical Guide to Combinatorial Chemistry, edited by A. W. Czarnik and S. H. DeWitt, American Chemical Society: Washington DC, 1997.