Chem 162A-B/262A-B
Drug Design
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Chem 162A-B/262A-B |
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Dr. Kalju Kahn
Office: PSB-N 2623
Office hours: Mon 10:30-11:30 PM, and Tue 4:30-5:30 PM
Phone: 893-6157
E-mail: kalju@chem.ucsb.edu
Website: http://www.chem.ucsb.edu
To teach principles that govern the process of modern drug discovery and development. Students in the course follow a path similar to that taken by real-life drug developers by learning important elements of the drug design process in a logical order.
Chem 162A, the first in the two-course series focuses on principles of rational drug design. Topics covered include target identification and validation technologies, generation and screening of chemical libraries for finding lead compounds, and modern medicinal chemistry approaches for ligand-based lead optimization. We will cover membrane-bound ion-channels and receptor proteins, and discuss strategies for finding agonists and antagonists for these types of targets.
The second course in the series, Chem 162B, will be taught in the Spring of 2012. The latter course focuses on structure-based drug design. It will outline experimental and computational methods for the study of ligand-protein complexes, and discuss how the knowledge of the three-dimensional structure of the active site helps in the lead optimization process. Chem 162B will also cover approaches used to design competitive and mechanism-based inhibitors based on the mechanistic understanding of enzyme catalysis. Finally, issues of pharmacokinetics and drug metabolism will be dealt with. Students are allowed to take Chem 162B/262B without taking Chem 162A/262B this academic year.
Lecture: MWF 8:00-8:50 Place: Phelps 1508
Computer Lab: Open day access Place: Chem 1153
| Syllabus | General information about the course. | |
| Textbook | The Organic Chemistry of Drug Design and Drug Action by Richard B. Silverman (Second Edition) | Amazon |
| Textbook | An Introduction to Medicinal Chemistry (Fourth Edition) | Amazon |
| Sample Lecture | Target Validation. (No Password Needed) Warning: Large File | PDF WAV |
| Last Years | Drug Design 162A (by Dr. Kalju Kahn) website for Fall 2009 | Link |
| Last Years | Drug Design 162B (by Dr. Kalju Kahn) website for Winter 2010 | Link |
| Exam | Midterm Preparation Guide | |
| Exam Key | Midterm Exam Key (Winter 2012) | |
| Exam | Final Preparation Guide | |
| Exam Sample I | Sample questions with answers from Spring 2004 | |
| Upload | Submit your assignments as PDF files | Link |
| Exam Key | Chem 162A Final Key, Winter 2012 |
Course notes will be posted here before 7:30 a.m. of the lecture day. The lecture slides are password-protected. Contact your instructor to obtain the password.
| Notes | Lecture Notes. Powerpoint Pages in PDF | Acrobat |
| Jan 9 | Overview of the course. History of Drug Design. | |
| Jan 11 | Rational Drug Design: Overview of Approaches | |
| Jan 13 | Diseases and the Biological Concept | |
| Jan 20-23 | Target Validation: Principles | |
| Jan 23 | Target Validation: Pre-Genomic Methods | |
| Jan 26 | Target Validation: Post-Genomic Methods | |
| Jan 27 | Target Validation Tutorial | Link |
| Jan 30 | Receptors as Drug Targets: General Overview | |
| Feb 1 | Receptors as Drug Targets: Ion Channels | |
| Feb 3-6 | Receptors as Drug Targets: GPCRs | |
| Feb 8 | Study of Membrane Receptors | |
| Feb 13 | Nuclear Hormone Receptors | |
| Feb 13 | Assays | |
| Feb 15 | Combinatorial Chemistry | |
| Feb 24 | Ligand-based drug design and optimization | |
| Feb 27 | Ligand-based drug design and optimization | |
| Feb 29 | Optimization of ADME properties | |
| March 5-7 | Fragment-based drug design and optimization | |
| March 9-12 | QSAR | |
| April 2 | Enzymes as Drug Targets | |
| April 4 | Enzymes: General Features | |
| April 6 | Enzymes: Principles of Catalysis | |
| Apr 9 | Enzymes: Mechanism and Kinetics | |
| Apr 13 | Modeling of chemical reactions and transition state analogs | Link |
| Apr 16 | Enzyme Inhibition | |
| Apr 18 | Mechanism-Based Enzyme Inactivation | |
| Apr 20 | Structure-Based Drug Design: Intermolecular Interactions | |
| Apr 23 | Structure-Based Drug Design: Thermodynamics | |
| Apr 25 | Visualization of Electrostatic Potential Surfaces | Link |
| Apr 27 | Structure-Based Drug Design: Protein Structure Analysis | |
| Apr 30 | Structure-Based Drug Design: Docking | |
| May 4 | Structure-based Drug Design: Docking | Link |
| May 7-14 | Structure-Based Drug Design: Modeling Protein Flexibility | |
| May 15-17 | Pharmacokinetics and ADMET Challenges | |
| May 21 | Drug Metabolism: Principles | |
| May 23 | Drug Metabolism: P450 | |
| May 25 | P450 Pharmacogenomics: Drug Toxicity and Drug-Drug Interactions | |
| May 30 | Prodrugs and Drug Delivery | |
| June 1 | Nucleic Acid Drugs | |
| June 4 | Job Options, Marketplace, and FDA |
| Literature | Required reading in PDF | Acrobat |
| General | From Serendipity to Rational Drug Design | |
| History | Drug Discovery: A Historical Perspective | |
| Future | Drug Research: Myths, Hype and Reality | |
| Targets | Antibacterial discovery strategy: GSK story | |
| Targets | How many drug targets are there? | |
| Targets | In Silico fishing for targets | |
| Receptors | Principles: Receptor Theory in Pharmacology (Kenakin, 2004) | |
| Receptors | Epibatidine: Impact on Nicotinic Receptor Research (Dukat & Glennon, 2003) | |
| Receptors | Orphan GPCRs (Wise, Jupe, and Rees, 2004) | |
| Receptors | How Antidepressants Block Neurotransmitter Reuptake | |
| CombiChem | High-diversity combinatorial libraries (Weber, 2000) | |
| CombiChem | Three-Component Synthesis of 2-Imidazolines (Orru et al, 2007) | |
| Ligand-Based | Chemistry of 1,4-benzodiazepines (Sternbach, 1971) | |
| Ligand-Based | Molecular Superposition (Miller, 1998) | |
| Ligand-Based | Fragment-Based Drug Discovery (Erlanson, 2004) | |
| Ligand-Based | Fragment-Based Drug Discovery (Erlanson, 2012) | |
| QSAR | Some observations on classical QSAR (Topliss, 1993) | |
| QSAR | From Narcosis to Hyperspace: The History of QSAR (Kubinyi, 2002) | |
| Enzymes | Enzymes and Enzyme Inhibition (Kahn) | |
| Enzymes | Transition State Binding | |
| Enzymes | Enzymatic Transition State Theory | |
| Enzymes | Protein Kinase Inhibitors | |
| SBDD | Principles of Biomolecular Recognition | |
| SBDD | The Process of Structure-Based Drug Design | |
| SBDD | The Many Roles of Computation in Drug Discovery | |
| SBDD | Protein-ligand docking: Current Status and Future Challanges | |
| SBDD | High-throughput docking | |
| SBDD | High-throughput docking: thyroid hormone receptor | |
| Metabolism | Coupled Bioreactor-HPLC-MS metabolite analysis of SERMs | |
| Prodrugs | Lessons Learned from Marketed and Investigational Prodrugs | |
| Drug Delivery | Targeted Nanoparticles for Cancer Therapy |
Suggested literature can be found now on a separate page
The assignments are posted one week before the due date. Answers shall be submitted electronically no later than the midnight of the due date.
| Assignments | PDF files | Acrobat |
| 1 | Enzymes. Catalysis and Inhibition. | |
| 4 | Pharmacokinetics, ADMET Challenges | |
| 5 | Drug Metabolism, Prodrugs, Drug Delivery |
The assignment keys are typically posted one week after the due date.
| Keys | PDF files | Acrobat |
| 1 | Enzymes: Mechanisms & Inhibition | |
| 2 | Electrostatic Potential Maps: Small Molecules | Link |
| 2 | Visualization of Chorismate Mutase Active Sites | |
| 3 | Target-Based Drug Design: Docking | Link |
| 4 | Pharmacokinetics, ADMET Challenges | |
| 5 | Drug Metabolism, Prodrugs, Drug Delivery |
The project milestone guides are typically posted week and a half before they are due.
| Project Tips | General Guidelines to Project Development |
Students in this course encounter many terms which have specific meaning in the context of drug design and medicine. You may find our glossary helpful when reading some of the assigned papers. If you encounter a term that is not in this dictionary, you could try a specialized medicinal chemistry glossary at www.chem.qmw.ac.uk/iupac/medchem ,an on-line dictionary at www.dictionary.com or an on-line encyclopedia at www.wikipedia.com . Feel free to send any additions and suggestions to Kalju Kahn
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Modern Drug Discovery
Nature Reviews Drug Discovery
Drug Discovery and Development
Drug Design Lecture Notes by Dr. Hugo Kubinyi
Oxford Drug Resistance Group Lectures
Calcium Channel Blockers
Brain Chemistry
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An Overview of Marine Drug Discovery
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