Chemistry 437/537 – Biological and Medicinal Chemistry – Spring 2013
TENTATIVE SYLLABUS
The objectives of this course are to:
-illustrate the central role of molecular structure in modern medicinal chemistry
-give students an appreciation for the many roles of chemistry in drug development
-provide an advanced understanding of weak interactions and hands-on experience with drug design
-give students a detailed understanding of the biomolecular targets that drugs act upon
-teach how the interactions of drugs with the body can be understood on a molecular level
Lectures: MR 8:30–11:00, ROOM TBA.
Instructor: Dr. Fraser Hof, Elliott 233c,
Office Hours: TBA
Grading: / Chem 437 / Chem 537Tests (6) / 50% / Tests (6) / 50%
In-class group presentation on a drug / 20% / Research proposal / 50%
Edited term paper on a biological target / 40%
Details and dates for the tests and assignments will be given in class. One test will be delivered at the end of each of the six sections (see list of topics). Weight from tests missed with a legitimate excuse will be transferred to the other tests.Make-up tests will not be offered.
Approximate basis for letter grades:
A+90-100A85-90A-80-84
B+75-79B70-74B-65-69
C+60-64C55-59D50-54
Course Website: serve as a repository for supplementary material, includingpowerpoint figures used in class.
is the course blog, to be used for anonymous feedback and discussion throughout the term.
Required materials:
There will be no text for the course.The book Molecules and Medicine (Corey, Kürti, and Czakó) is an excellent resource that provides informal summaries that cover the targets, design, development, and pharmacology for many important drugs.
LIST OF TOPICS FROM 2011 — to be adapted fro 2013.
Topic / Lecture # (approx.)1. Introduction
- History of drug development / 1
- The chemical essentials of biomolecules: pKa, ionization, and chemical properties
- An overview of drug development / 2
- Paradigms for lead discovery and optimization
Screening of natural or synthetic libraries
Structure-based drug design
Fragment-based approaches
2. Assays and the meanings of their outputs / (4 lectures)
- Reversible binding and its associated measurable quantities / 2
“G, Kassoc., Kd, Ki”
- Direct measures of Kd, Ki: ITC, SPR/Biacore, ELISA, NMR
- Assays of enzyme inhibition: the math behind Vmaxand IC50
Absorbance of chromogenic substrates: a glycosidase assay / 3
FRET: theory, and an exemplary protease assay
Coupled assays - Kinase activity measured by luminescence
- Fluorescence polarization assays for protein-protein interactions: “Kd, EC50” / 4
- Assays of receptor binding/function
Radioisotope incorporation assays: “% inhibition”
Radioisotope displacement assays: “Kd” / 5
3. Weak interactions in biol. and med. chem. / (8 lectures)
Weak interactions
- Protein folding, drug binding, and analysis of binding energetics / 5
- Electrostatic and dipolar interactions / 6
- Dispersive forces / 6-7
- Hydrogen bonds / 7-8
- Aromatic interactions / 9
- Cation-π interactions / 10
- The hydrophobic effect / 10-11
But does it fit? Understanding the shapes of small molecules.
- Preorganization and binding energetics / 11
- Inhibitor shapes: a) calculations and b) conformational analysis / 11-12
Molecular modeling and inhibitor design / 12
4. Drug targets & mechanisms of action / (7 lectures)
- What’s a drug target anyway? How many are there? What makes a good drug target? / 12
- Target identification chemistry / 13
Important target classes and drug development examples
- G-protein coupled receptors (GPCRs)
Developing a pharmacophore model without structure
- G-protein coupled receptors (GPCRs) continued / 13 (14 = test; 18
- Nuclear receptors (+ in-class exercise on pharmacophores and structure) / 19
- Penicillin binding proteins / 20
- Drug targets on the rise: Proteases, Synthases / 20, 21
- Inverting the situation: biomolecules as drugs, not targets
Therapeutic antibodies (against Receptor Kinases)
siRNA / 22
23
5. Pharmacology / (5 lectures)
Pharmacokinetics — the body’s action on the drug / 23
Key parameters: Clearance, Volume of distribution, AUC, half-life / 23 (24 = test), 24
- Absorption (dosing methods, first-pass clearance, bioavailability, in vitro assays, structural cues for oral availability, pro-drugs)
- Distribution (plasma protein binding, cell permeability, target organs/BBB)
- Metabolism (liver enzymes, common metabolic rxns,)
- Excretion / 25
26
27
- Structural predictions of drug-likeness: Lipinski’s rules and Veber’s rules / 27
(28 = test)
6. Case studies in medicinal chemistry
In-class presentations to be delivered by 437 students / 6 lectures
(Mar 18–30)
- Each talk will summarize scientific work on a single prominent drug.
Final day — test#6