Principles of Drug Design

Transcription

1 Advanced Medicinal Chemistry II Principles of Drug Design Tentative Course Outline Instructors: Longqin Hu and John Kerrigan Direct questions and enquiries to the Course Coordinator: Longqin Hu I. Introduction to The Drug Discovery/Development (Hu) 1 lecture 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 II. Approaches to New Drug Discovery (Hu) 2 lectures 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

2 Course Outline Page 2 III. The Chemistry of Drug Absorption, Distribution, Metabolism and Elimination: Issues Related to Drug Development (Hu) 2 lectures A. Administration and Absorption 1. Form of Drug 2. Routes of Administration 3. Models of Absorption Passive and Facilitated Thermodynamics and Kinetics 4. Bioavailability B. Drug Distribution 1. Physiological compartments 2. Protein binding C. Drug Metabolism Biotransformation (Brief Review) 1. Site of metabolism 2. Chemistry of phase I Metabolism 3. Chemistry of phase II Metabolism 4. Consequences of Metabolism 5. Metabolic inhibition and induction D. Elimination 1. Lungs 2. Kidney 3. Biliary excretion IV. Pharmacomodulation (Hu) 1 lecture A. Introduction and Rationale B. Increased Chemical Stability C. Altered Solubility D. Improved Taste and Compliance E. Increased Absorption F. Decreased Metabolism G. Increased Selectivity H. Enhanced protein binding I. Enhanced BBB penetration J. Tissue-specific distribution V. Enzymes as Targets of Drug Design (Hu) 4 lectures A. Enzyme kinetics 1. The Michaelis-Mention Equation 2. Steady state of an enzyme-catalyzed reaction 3. Validity of the Steady-state assumption

3 Course Outline Page 3 4. Graphs of the Michaelis-Mention Equation 5. Practical aspects of kinetic studies B. Enzyme inhibition and activation 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 1. Transition state analogues 2. Mechanism-based inhibitors 3. Affinity labels VI. Receptors as Targets of Drug Design (Hu) 3 lectures 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 VII. Design of Peptidomimetics (Hu) 1 lecture A. Limitations of Peptides as Drugs B. Cyclization of Peptides C. Constrained Amino Acids D. Molecular Mimics for Secondary Structures E. Amide Bond Isosteres F. Nonpeptide Ligands for Peptinergic Receptors VIII. 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+)

4 Course Outline Page 4 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 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

5 Course Outline Page 5 IX. Combinatorial Chemistry (Kerrigan) 4 lectures 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