MEDC 310: Medicinal Chemistry and Drug Design

Medicinal Chemistry and Drug Design (MEDC/CHEM 310)

Spring 2009 (3 credits)

Meetings:

MEDC 310 will meet Mondays and Wednesdays at 7:00-8:15 pm in Room 1160 of the Temple Building.

Instructors:

Medicinal Chemistry: Dr. U.R. Desai, Dr. M. Dukat, Dr. K.C. Ellis, Dr. R.A. Glennon, Dr. J.C. Hackett, Dr. G.E. Kellogg, Dr. L.B. Kier, Dr. J.P. Rife, Dr. M.K. Safo, Dr. R.B. Westkaemper, Dr. B.E. Windle, Dr. R. Young, Dr. S. Zhang and Dr. Y. Zhang

Chemistry: Dr. N.P. Farrell and Dr. M.C. Hartman

Pharmaceutics: Dr. F.D. Boudinot, Dr. H.T. Karnes, Dr. M. Sakagami, Dr. J. Venitz and Dr. S. Wu-Pong

Pharmacy: Dr. B.L. Bukaveckas

Dr. Kellogg (Biotech I, MCV; 828-6452; Glen.Kellogg@vcu.edu) is the course coordinator; Dr. Hackett (Biotech I, MCV; jchackett@vcu.edu) is the co-coordinator.

Goals and Objectives:

MEDC 310 is designed to expose undergraduate Chemistry, Biology and Pre-medicine majors to the history, theory and practice of Medicinal Chemistry. The course will emphasize a combination of fundamentals and applications of drug design and development. In particular, the molecular aspects of drug action (chemical, physical, and biological) will be discussed. Special emphasis will also be placed on the methods used by Medicinal Chemists to design new drugs to treat significant disease states, and by Pharmaceutical Chemists to develop, deliver and monitor effective therapeutic agents.

At the completion of this course:

1. The student should be able to relate basic concepts in a variety of drug classes to their biological action.

2. The student should know the chemical basis for some of the known mechanisms of drug action.

3. The student should understand the role of molecular modification in the development of new drugs; its successes, shortcomings and failures.

4. The student should understand the role of de novo and molecular modeling techniques in the development of new drugs.

5. The student should be able to relate chemical structure to biological availability, biological activity, and routes of delivery/metabolism for some of the more important pharmacological classes.

Prerequisite:

The student is expected to have completed a two semester sequence in Organic Chemistry. (Biochemistry or Cell Biology is recommended.)

Attendance:

Roll will not be taken on a regular basis. You are urged to attend all classes. If you rely on another student's notes you will not get the same educational experience as attending the class yourself.

Grading:

There will be two exams during the semester and a final exam. The three exams will be weighted equally. The dates for the exams as indicated in the schedule are firm and will not be changed except under the most unusual circumstances. A student wishing to have his/her exam regraded must do so within one week following the date the examination was returned.

Text:

There is no formal text for the course, but books, articles and other materials may be placed on reserve as appropriate at Cabell Library by the instructors.

Evaluation:

Students will be given a formal opportunity to evaluate this course and the instructors. The evaluation will be reviewed by the course instructors, course coordinator and the department chairman. Informal comments and suggestions are welcome at any time.

Course Web Page:

See http://www.phc.vcu.edu/310/ for an expanded syllabus, schedule updates (e.g., weather, related changes), posting of course materials and examples of previous exams. Note, however, the course does not follow the same schedule each year and the lectures may be given in different order, by different instructors, or cover different topics. The previous exams are only a useful study guide, not a replacement for course attendance and diligent note-taking.

Official Policies:

The Americans with Disabilities Act of 1990 requires Virginia Commonwealth University to provide a 'reasonable accommodation' to an individual who advises us of a physical or mental disability. If you have a physical or mental limitation that requires an accommodation or an academic adjustment, please arrange a meeting with the coordinator at your earliest convenience.

All course materials and performances are copyrighted by their authors. Students wishing to record lectures in any format must obtain the explicit permission of each presenter. Electronic posting or re-posting of any course material in a publicly accessible forum is prohibited.

Schedule:

Jan 12

G.E. Kellogg:

Course Introduction: Historical & Modern Medicinal Chemistry (notes)

A.	Definition of Medicinal Chemistry
B.	Fields that Interface with Medicinal Chemistry
C.	History
	1. Synthesis of Living Molecules
	2. Historical Figures
	3. Structure of DNA and Proteins
D.	Drug Design and Drug Screening
E.	Molecular Structure
	1. Atoms of Life
	2. Molecules Involved in the Life Process
	3. Stereochemistry and Handedness
F.	Physical Chemistry in Drug Action and Drug Design

Jan 14

Y. Zhang:

Physicochemical Properties in Relation to Biological Activity (notes)

A.	Drug to Drug Distribution and Pharmacologic^M Response
	1. Absorption
	2. Protein Binding
	3. Drug Metabolism
B.	Acid/Base, pH Effects on Structure
	1. Drug Absorption
	2. Membrane Structure
C.	Properties and Biological Activity
	1. Partition Coefficients
	2. Drug-Receptor Interactions
	3. Isosterism
	4. Steric Features and Electronic Properties of Drugs
	5. Conformational Aspects of Biological Activity
	6. Optical Isomerism and Biological Activity

Jan 21

R.A. Glennon:

Brain, CNS, and Receptors

A.	Neurotransmission
	1. The Neuron
	2. Neuronal Architecture
	3. Neuronal Function
B.	Neurotransmitters and Receptors
	1. Definitions and Description
	2. Neurotransmitter Biosynthesis and Metabiolism
C.	Neuronal Sites of Drug Action

Jan 26

M. Dukat:

Receptor Theory and Signaling

A.	Drug Receptors / Receptor Structure
	1. Ion Channel Receptors
	2. G-Protein Coupled Receptors
B.	Second Messenger Systems
	1. Drug-Receptor Interactions and Receptor Theory
	2. Agonists
	3. Antagonists

Jan 28

R.A. Glennon:

Drugs and the Brain (Selected Examples of Drug Classes and Actions)

A.	G-Protein Receptor Agents
	1. Neuroleptic (Antipsychotic) Agents
	2. Anti-Parkinson Agents
B.	Ion Channel Receptor Agents
	1. Anxiolytic (Antianxiety) Agents
	2. Others

Feb 2

R. Young:

Drug Discrimination and Other Behavioral Assays

A.	Methodology
B.	Subjects
C.	Dose and Time Parameters
D.	Nature of the Stimulus
	1. Stereoselectivity
	2. Specificity
E.	Locus and Mechanism of Action
F.	Structure-Activity Studies

Feb 4

J.P. Rife:

Antibiotics that Inhibit Translation (notes)

A.	Overview of Translation
B.	Structure of the Ribosome
C.	Specific Drugs

Feb 9

F.D. Boudinot:

What happens to the drug in the body? - Absorption, Distribution, Metabolism and Excretion (ADME)

A.	Routes of Administration of Drug
B.	Absorption
C.	Distribution
	1. Protein Binding
D.	Metabolism
	1. Phase and Phase II pathways of drug metabolism
	2. First pass hepatic and presystemic metabolism
E.	Excretion
	1. Urinary
	2. Biliary

Feb 11

Y. Zhang:

Natural Products and Drugs (notes)

A.
	1.
	2.
B.
	1.
	2.
	3.
	4.
C.
	1.
	2.
	3.
D.

Feb 16

B. Windle:

Bioinformatics (notes)

A.	Microarray Technology
B.	Gene Expression Profiling
C.	Pattern Recognition
D.	Applications
	1. Disease Characterization
	2. Drug Development

Feb 18

EXAM 1:

Material through February 11
Download PDF of Previous Years' Exams: 2007, 2008 (key), 2009 (key)

Feb 23

N.P. Farrell:

Metal Complexes in Medicine (notes)

A.	Background
	1. Chemistry of Metal Species
	2. Biochemistry
	3. Structure-Activity Relationships
B.	Clinical Drugs
	1. Anticancer Platinum Agents
	2. Antiarthritic Gold Complexes
	3. Lithium drugs
C.	Metal-containing Imaging Agents

Feb 25

M.C. Hartman:

In vitro Selections (notes)

A.
	1.
	2.
	3.
B.
	1.
	2.
	3.

Mar 2

K.C. Ellis:

Cancer Biology and Natural Products (notes)

A.
	1.
	2.
B.
	1.
	2.
	3.
	4.
C.
	1.
	2.
	3.
D.

Mar 4

G.E. Kellogg:

Molecular Modeling and Computer-Aided Drug Design (notes)

A.	What is Molecular Modeling?
	1. Extrapolation of Known to Unknown
	2. Visualization and Computer Graphics
	3. Observable Properties
B.	Key Techniques of Modeling
	1. Quantum Mechanics
	2. Molecular Mechanics
	3. 3-D QSAR
	4. Small Molecule Data Base Searches
	5. "Docking" and De Novo Drug Design Methods
C.	HINT and LogP_o/w

Mar 9, 11

S P R I N G B R E A K

Mar 16

J.C. Hackett:

Protein, Nucleic Acid Structure and Modeling (notes)

A.	Basic Elements Contributing to 3-D Structure
B.	Experimental Determination of Macromolecule Structure/Structure Databases
C.	Sequence Homology and Homology Based Modeling
D.	Modeling Ligand-Protein Association
	1. Docking Methods
	2. Molecular Mechanics
	3. Molecular Dynamics

Mar 18

R.B. Westkaemper:

Rational Drug Design from Enzyme Inhibitors

A.	Introduction
	1. Mechanistic Classes of Enzymes
	2. Principle of Mechanistic Generalization
	3. Nature and Extent of Structural Data
B.	Properties of Enzyme Systems
	1. The Problem: Chemical Ester/Amide Hydrolysis
	2. Enzyme Structure
	3. Enzyme Kinetics
	4. Rational Inhibitor Design
C.	Angiotensin Converting Enzyme (ACE) - Hypertension
	1. Hypertension
	2. Renin-Angiotensin Pathway
	3. Carboxypeptidases
	4. ACE
D.	HIV Protease
	1. Role of HIV Protease in Virus Maturation
	2. Acid Proteases
	3. Structure, Specificity and Mechanism of HIV Protease
	4. Inhibitors
	5. Clinical Outlook

Wk of Mar 23

G.E.K., J.C.H. and R.B.W.:

Molecular Modeling Laboratory (Time and Day TBA, Suite 212, Biotech I, MCV Campus)

A.	Visualization/Building of Small Molecules
B.	Molecular Mechanics and Dynamics
C.	Three-Dimensional Structure of Biomacromolecules
D.	Studying Docking and Other Interactions

Mar 30

S. Zhang:

Alzheimer's Disease (notes)

A.
	1.
	2.
	3.
B.
	1.
	2.
C.
D.

Apr 1

S. Wu-Pong:

Design and Delivery of Nucleic Acid Drugs

A.	Types of Nucleic Acid Drugs
	1. Gene Therapy
	2. Oligonucleotides
	3. Ribozymes
B.	Limitations of Nucleic Acid Drugs
	1. Stability
	2. Transport
C.	Types of Structural Modifications
D.	Delivery Strategies

Apr 6

EXAM 2:

Material through Mar 30
Download PDF of Previous Years' Exams: 2007, 2008 (key), 2009 (key)

Apr 8

L.B. Kier:

Quantitative Structure Activity Relationships (notes)

A.	Property QSAR
	1. Parameters
	2. Models
	3. Interpretation
B.	Structure QSAR
	1. Chemical Graph and Molecular Connectivity
	2. Kappa Shape Indices
	3. Electrotopological Indices
C.	Overview and Future Developments

Apr 13

B. Lewis:

Pharmacogenomics: Personalized Medicine (notes)

A.
B.
C.

Apr 15

M.K. Safo:

Sickle Cell Anemia (notes)

A.	Origin and Cause of the Disease
	1. Physiological
	2. Genetics
B.	Hemoglobin S Chemistry
	1. Hemoglobin Equilibrium
	2. Structure of HbS and Polymerization
C.	Possible Methods for Finding a Treatment or Cure
	1. Cures: Gene Engineering/Marrow Transplants
	2. Treatments: HbF Gene Manipulation, Cell Volume Expansion, Stereospecific Drug Interaction with HbS

Apr 20

H.T. Karnes:

Analytical Chemistry in Drug Development (notes)

A.	Technologies Applied
	1. Chromatography/Electrophoresis
	2. Tandem Mass Spectroscopy
	3. Laser Induced Fluorescense
	4. Radiation Spectroscopy
B.	Problems Encountered
	1. Low Level Bioanalysis
	2. Drug Substance and Formulation Testing
C.	The Regulatory Environment
	1. Validation and Control of Analytical Methods
	2. Good Laboratory Practices

Apr 22

J. Venitz:

Integrated Drug Development: From the Bench to the Bedside (notes) Additional Materials: Lecture Outline, Pre-Clinical Development, Clinical Development, Labeling, Approval, PDE5 Inhibitors in ED, Sildenafil Development

A.	Non-clinical Testing
	1. Toxicological Assessment
	2. Assessment of Specific and General Pharmacology
	3. Assessment of Pharmacokinetics and Pharmacodynamics (PK/PD)
	4. Formulation Development
B.	Clinical Testing
	1. US Regulatory Requirements
	2. Phase I Clinical Trials (Safety & Toleration)
	3. Phase II Clinical Trials (Efficacy & Dose)
	4. Phase III Clinical Trials (Pivotal Proof)
	5. Phase IV Clinical Trials (Surveillance)
C.	RSR13 - A Novel Drug Discovered and Developed at VCU on the way to the Clinic

Apr 27

U.R. Desai:

Coagulation and Anti-coagulation

A.	Clot Formation
	1. Why?
	2. Physiology and Chemistry
B.	Clotting Cascade
	1. Chemistry of Activation
	2. Amplification
C.	Inhibition of Clot Formation
	1. Why?
	2. Natural Inhibitors
	3. Inhibitors as Drugs

Apr 29*

M. Sakagami:

Factors Controlling Drug Delivery via the Lung

A.	Environmental and Pharmaceutical Driving Forces Causing Innovation
	1. New Delivery Devices
B.	Lung Disposition following Small Molecule Inhalation
	1. Form (powder, solution, excipient effects)
	2. Importance of Drug Physical Chemistry
	3. Effect of Lipophilicity on Duration of Effects
C.	Lung Disposition following Large Molecule Inhalation
	1. Importance of Regional Deposition
	2. Study Methods excluding Metabolism
	3. Kinetic Models Explaining Protein Absorption

May 4

EXAM 3:

Material through end of course
Download PDF of Previous Years' Exams: 2007, 2008 (key)

*This is "Reading Day", but it does not apply to evening courses on the Monroe Park Campus.