Medicinal Chemistry Chem 5398 Professor: J. D. Buynak Phone: ex Overview

Transcription

1 Medicinal Chemistry Chem 5398 Professor: J. D. Buynak Phone: ex Overview The pharmaceutical industry has developed around the need to produce safe, effective products to treat disease and relieve pain. While some of these substances are isolated from natural sources, nearly all involve some sort of synthetic structural manipulation before they are distributed, and an increasing number are purely synthetic. Thus it should not be unexpected that approximately half of the scientists employed by the pharmaceutical industry are chemists and that this same industry is, by far, the largest employer of chemists. Likewise, the practicing physician has an increasing number of drugs in his/her armamentarium. These chemical products are continually improving in efficacy and, with a few notorious exceptions, in safety. The science of medicinal chemistry has made a dramatic contribution to our quality of life and to our life expectancy itself. Many factors have contributed to the dramatic development of this field. Through the science of biology, the disease processes become better understood and prospective biological drug targets are identified. Biochemists have elucidated the precise molecular structure of those drug targets and developed assays for the rapid screening of new drug candidates. Molecular biologists have defined the structure of the genome which is presently being interpreted into structural proteomic information, thus making it again possible to know the structures of the targets of drugs. The role of the chemist has been to synthesize and, in many cases, to design the drugs themselves. As we will see throughout the semester, the speed at which each of these processes can be accomplished has increased exponentially. This rapid pace of change means that textbooks in this area must be frequently updated. Thus, we will often be forced to rely on the research literature for up-to-date information. It is my goal in this semester to provide you with a current overview of this increasingly important scientific area. I believe that such knowledge will be of use to you regardless of what area of science or medicine you may pick for your career. I have selected two textbooks for the semester. The first, An Introduction to Medicinal Chemistry by Graham L. Patrick, provides a current analysis of the methods of drug discovery, and is being used as an interesting read for the undergraduates. The second, Block and Beale's Organic, Medicinal, and Pharmaceutical Chemistry, will provide a more comprehensive and detailed description of the specific classes of drugs. I plan to use both extensively throughout the semester. 1

2 Approaches to the Topic of Medicinal Chemistry and Level of Course: We will approach the topic from many different angles simultaneously. I will begin at the chemical level, progress to elementary biochemistry, move into a discussion of drug design and discovery, and finish with a discussion of as many different classes of drugs as we can fit in. You can count on the fact that I will bring in a chemical approach to every subject under consideration, since that is my background. You and I should both realize that the students in this class have widely different backgrounds, thus making it difficult for me to challenge the most informed and yet not lose the beginners. I promise to do my best on both fronts and I ask for your patience, especially from those at both ends of the spectrum. Also please keep in mind that medicinal chemistry is a vast and extremely complex subject. I know of places where students take Medicinal Chemistry over three semesters and are instructed by three separate professors. However, I also know that this is the only class of its kind offered in the DFW area, and one of only two that I am aware of in the State of Texas. We will attempt to cover everything from the ground up in one short semester. Grading: I have decided on having three exams, including the final along with a term paper, each worth 25% of your grade. Subjects for the term paper will be discussed as the semester progresses. Important Dates: Sept. 7 Term Paper Topic Choice Due (lecture on data base searching: SciFinder and Entrez) Sept. 14 Term Paper Choices Approved Sept. 21 Initial Report on beginning term paper research handed in Sept. 28 Exam #1 Oct. 9 Outline and preliminary draft of term paper handed in (with photocopy of refs, please make yourself a copy, since I will not return photocopy) Oct. 12 Fall Break Nov. 2 Exam #2 Nov. 3 Last day to drop a class Nov. 9 Term papers due Nov. 25 Thanksgiving Dec. 2 Last day of this class Dec. 10 Final Exam (8:00 AM) 2

3 Course Outline I. Introduction A. What are drugs? B. What are the molecular targets of drugs? 1. Enzymes 2. Receptors II. Enzymes as drug targets A. Protein structure B. Some examples of drug action at carrier and structural proteins C. Peptides as drugs D. Antibodies as drugs E. Enzymes are biological catalysts F. The active site of the enzyme G. The crystallographic study of proteins 1. The Protein Data Bank (PDB) 2. The visualization of protein structures a) Downloading structure b) Visualization with Sybyl using unix-based computers H. The active site of the enzyme 1. Substrate binding 2. Inhibition a) Competitive (reversible) inhibitors b) Non-competitive (allosteric) inhibitors c) Irreversible inhibitors 3. See also A.G. Chap. 2, pages I. Regulation of enzymes by kinases J. Medicinal uses of enzyme inhibitors K. Enzyme Kinetics III. Receptors as targets for drugs A. What is a receptor and how does it work? B. Agonists/Antagonists and their design C. Families of Receptors IV. Nucleic acids A. DNA 1. Structure of DNA 2. Drugs that work on DNA B. RNA 1. Structure of RNA 2. Drugs that work on RNA C. Drugs related to nucleic acids and nucleic acid building blocks V. Drug discovery and drug development 3

4 A. Identifying drug targets B. Finding and developing a lead compound C. Binding interactions in the active site D. Clinical Trials of a new drug VI. Drug Design (Preliminary Structure-Based Design) VII. Pharmacokinetics A. Metabolism of Drugs 1. Designing Drugs to resist metabolism 2. Designing Prodrugs B. Methods of Administering Drugs VIII. Quantitative Structure-Activity Relationships (QSAR) IX. Combinatorial Synthesis X. Computers in Medicinal Chemistry XI. Antibacterial Agents A. β-lactam Antibiotics: Inhibit bacterial cell wall synthesis 1. Penicillins 2. Cephalosporins 3. Carbapenems 4. β-lactamase Inhibitors B. Bacterial Agents Which Interfere With Protein Synthesis A. Aminoglycosides B. Macrolides C. Tetracyclines C. Bacterial Agents Which Act on Nucleic Acid Transcription and Replication - Quinolones and Fluoroquinolones D. Drug Resistance XII. Cholinergics, Anticholinergics, and Anticholinesterases XIII. The Adrenergic Nervous System XIV. The Opium Analgesics XV. Cimeticine, A Rational Approach to Drug Design Other: * Disability Accommodations: Students needing academic accommodations for a disability must first contact Ms. Rebecca Marin, Coordinator, Services for Students with Disabilities ( )* to verify the disability and establish eligibility for accommodations. They should then schedule an appointment with the professor to make appropriate arrangements. (See University Policy No. 2.4.) > > * Religious Observance: Religiously observant students wishing to be absent on holidays that require missing class should notify their professors in writing at the beginning of the semester, and should discuss with them, in advance, acceptable ways of making up any work missed because of the absence. (See University Policy No. 1.9.) 4

5 > > * Excused Absences for University Extracurricular Activities: Students participating in an officially sanctioned, scheduled University extracurricular activity will be given the opportunity to make up class assignments or other graded assignments missed as a result of their participation. It is the responsibility of the student to make arrangements with the instructor prior to any missed scheduled examination or other missed assignment for making up the work. (University Undergraduate Catalogue) 5