Medicinal Chemistry
CHEM 4170
Instructor: Dr. Kent Gates
University of Missouri-Columbia
Office: 325.1 Chemistry Bldg.
email: GatesK@missouri.edu
Worldwide Web:
http://www.chem.missouri.edu/GatesGroup/Research.html
Office Hours: Mon 3:00-4:00 PM
Course information
Current Assignments: See syllabus for reading assignment.
Click Here For a pdf Version of Course Syllabus
Click Here For a pdf Version
of the Protein Visualization Assignment (Due on the First Friday of April)
Click Here For a pdf Version
of Drug Research Assignment (Due on the Last Day of Class)
We will use organic chemistry in this course. For a free organic text go to: http://www.ochem4free.com
"Binding" or "Molecular Recognition"
typically involves "Convergent Assembly" of various weak forces.
Distance, alignment and shape complimentarity are important in noncovalent
binding. Click Here for a paper that describes the design and characterization
of organic "receptors" that selectively bind small organic molecules.
Click here for a pdf version of an article
that describes the importance of HYDROPHOBIC EFFECTS in drug-macromolecule
binding reactions. You can read the whole thing... but Sections 1, 5 and 6 (the
introduction and conclusions) contain information that you should know.
Drug-Target Equilibrium Binding: Calculations showing how small changes
in the free energy of binding can cause significant changes in equilibrium
binding constants.
Click here for a pdf file that shows the chemical
structure of the common amino acid side chains
Click here for a pdf file that discusses
protein structure and protein folding
Click here for a nice paper that
describes a successful execution of "Structure-Based Drug Design".
Overview of solid-phase peptide synthesis.
For a review of carbonyl chemistry.
Click Here For a pdf Version an article about
"diversity oriented" chemical synthesis. The deliberate preparation
of complex libraries of organic molecules is a new tool in drug discovery.
Using Tags to "Decode" Combinatorial
Libraries.
Click here for a nice table of Log P values.
Courtesy of Professor Richard B. Silverman (Northwestern University).
An schematic overview of the typical "drug discovery roadmap".
Lipinski's Rule of Five (focus on pages 4-15.
Overview of the Hammett equation: use of QSAR in organic and medicinal chemistry.
Click here for an overview of the Hammett Equation (and
Tables of Hammett substitutent constants). Courtesy of Professor Richard
Loeppky (MU).
A review in which the authors estimate that only 10-15% of human proteins are likely to be "druggable" (that is they are disease related and can be effectively targeted by small molecules).
A quick review of Ka, pKa, and acid-base
chemistry
Problem Set One.
Answers to Problem Set One
Problem Set on Protonation.
Answers to protonation problem set.
Answers to Exam Number One, 2003
Answers to Exam Number One, 2004
Answers to Exam Number One, 2005
Answers to Exam Number One, 2006
Answers to Exam Number One, 2007
Answers to Exam Number One, 2008
Cartoon Examples of Receptors: Recognition of small molecules and signal amplification
Click here pdf file of a paper on the discovery of
prilosec
A nice cartoon of the proton pump. The target of drugs like tagament and prilosec.
Click here pdf file of a paper that
discusses how Caffeine works (it "hits" a receptor)
Click here for a graphic that shows how many
clinically used drugs "hit" each category of biological target
(receptor, enzyme, DNA, etc)
Problem Set Two
Answers to Problem Set Two
For a handout that discusses the kinetics and
mechanism of reversible enzyme inhibition (courtesy of Professor R. Leoppky,
MU)
For a handout that discusses the enzyme kinetics
and the kinetics of enzyme inhibition and inactivation (from: The Organic
Chemistry of Enzyme-Catalyzed Reactions, by R. B. Silverman)
For an excellent "case study" describing recent efforts toward the development of an inhibitor of the NS3 hepatitis C viral protease: the boceprevir story.
For a publication describing discovery of mechanism-based inactivator of the SARS 3CL cysteine protease.
Regarding development of affinity labeling agents against the bacterial cysteine protease SrtA
A paper describing the mechanism-based inactivation
of proteases and acetylcholinesterase (example from lecture)
Another paper on mechanism-based inactivation of
proteases and acetylcholinesterase
A paper from Larry Marnett's group describing
details of how aspirin "affinity labels" the active site serine of
COX2
A paper from the medical journal "The Lancet"
regarding the discovery of COX3 enzyme. Is COX3 the target for acetominophen?
Problem Set Three.
Answers to Problem Set Three.
Answers to EXAM TWO 2003.
Exam Two Answer Key, 2004.
Answers to Exam Two, 2005.
Exam Two Answer Key, 2006.
Exam Two Answer Key, 2007.
Exam Two Answer Key, 2008.
A nice review of DNA-targeted anticancer
drugs.
A recent review suggests that
"traditional" DNA-damaging cytotoxins will continue to be used for
quite some time in cancer chemotherapy.
A review discussing how natural
products have in the past, and can continue to, provide drugs and drug leads in
cancer chemotherapy.
A review of cellular responses to DNA
damage. Programmed cell death (apoptosis), cell cycle arrest, DNA
damage-induced transcription, and DNA repair.
Structures of Sequence-Specific DNA-Binding
Agents. Dervan's "Antigene" Agents.
Another paper about Dervan's Antigene
Agents (has a very nice picture of the DNA-drug complex).
Binding of Dervan's Antigene agents
to the biologically-relevant form of DNA: histones.
Tetracycline binding to the 30S ribosomal RNA.
Overview of RNA-targeted Small Molecules by
Y. Tor.
Electrostatic interactions of Neomycin
with RNA.
Agents that inactivate the ribosome in human cells are
toxic. Ricin.
Onconase is an enzyme targets tRNA molecules. Onconase is undergoing phase III clinical trials an an anticancer agent.
Bleomycin targets tRNA molecules.
A picture of a gramicidin-like membrane-spanning
channel. From Angew. Chem. Int Ed. Eng. 2002, 41, 4062.
A review of gramicidin A. Nice picture of the
channel on page two.
Discovery of magainin-like peptide
antibiotics produced by human damaged human skin. See reference 1 of this
article (Ann. Rev. Immunol. 1995, 13, 61-92) for a nice overview of
pore-forming antibiotic peptides produced by plants and animals.
Problem Set Four.
Answers to Problem Set Four.
You Can Find Some Medicinal Chemistry-Related
Websites on Gates' "Useful Links" Page
· •Back To Gates
Research Group Webpage