Biological Sciences 275B Spring 2005
Protein Structure Based – Drug Design
BSB 2210A, Thursday, 1:10-3:00 PM
Instructor:
Dr. Andrzej M. Krezel
phone: 322-2073
MRBIII/BSB 5270A
email: Andrzej.M.Krezel@Vanderbilt.edu
Office hours: see below
Textbook: see below
Student presentations of research from the literature will be the center of this course. Each
student will present twice. One presentation will be focused on the target protein structure and
another one on the drug design, but using a different target structure. Seminars will be presented
in an electronic format (PowerPoint or similar). The protein structure presentation should include
an interactive computer graphics component.
There is no textbook for this class. Structural biochemistry background can be found in
almost any biochemistry textbook, an example used in BSCI220, Fundamentals of Biochemistry
by Voet, Voet and Pratt. A helpful introduction to the concepts of drug design can be found in a
recent review by Kitchen DB, Decornez H, Furr JR, & Bajorath J. “Docking and scoring in
virtual screening for drug discovery: methods and applications” Nature Reviews Drug Discovery
3, 935-949 (2004).
There are no scheduled office hours. Students will meet with instructor at least once
before the presentation. In this meeting, the overall plan of the seminar, including drafts of all
slides will be discussed. Students can arrange any number of additional meetings.
There will be no exams. Grades will be calculated as follows: seminar presentations will
count 75%, and in-class activity 25%.
Emails @Vanderbilt.edu
Student1
Student2
Student3
Student4
Student5
Student6
Student7
Student8
Student9
Student10
Student11
Student12
Some useful web-links
PubMed bibliographical database
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
Protein Data Bank of 3D coordinates
http://www.rcsb.org/pdb/
Swiss-PDB Viewer molecular modeling software
http://www.expasy.org/spdbv/text/download.htm
Protein Explorer (used to be Rasmol) for PC (Mac version is cumbersome)
http://molvis.sdsc.edu/protexpl/frntdoor.htm
BSCI 275B 2005 - Syllabus
Date
Speakers and subjects
1. January 13 Organization, overview of the subject
2. January 20 Structure- Student1
Design – Student2
Palomer A, Pascual J, Cabre M, Borras L, Gonzalez G, Aparici M, Carabaza A,
Cabre F, Garcia ML, Mauleon D. Structure-based design of cyclooxygenase-2
selectivity into ketoprofen. Bioorg Med Chem Lett. 12, 533-537 (2002).
3. January 27 Structure- Student3
Design – Student4
Rastelli G, Pacchioni S, Sirawaraporn W, Sirawaraporn R, Parenti MD, Ferrari
AM. Docking and database screening reveal new classes of Plasmodium
falciparum dihydrofolate reductase inhibitors. J. Med. Chem. 46, 2834–2845
(2003).
4. February 3 Structure- Student5
Design – Student6
Kamionka M, Rehm T, Beisel HG, Lang K, Engh RA, Holak TA. In silico and
NMR identification of inhibitors of the IGF-I and IGF-Binding protein-5
interaction. J. Med. Chem. 45, 5655–5660 (2002).
5. February 10 Structure- Student7
Design – Student8
Meagher KL, & Carlson HA. Incorporating protein flexibility in structure based
drug discovery: using HIV-1 protease as a test case. J. Am. Chem. Soc. 126,
13276–13281 (2004).
Structure- Student9
Design – Student10
Ren J & Stammers DK. HIV reverse transcriptase structures: designing new
inhibitors and understanding mechanisms of drug resistance Trends Pharm. Sci.
26, 4-7 (2005).
6. February 17 Structure – Student11
Design – Student12
Vangrevelinghe E, Zimmermann K, Schoepfer J, Portmann R, Fabbro D, Furet P.
Discovery of a potent and selective protein kinase CK2 inhibitor by highthrougput docking. J. Med. Chem. 46, 2656–2662 (2003).
7. February 24 Structure – Student2
Design – Student1
Nantermet PG, Barrow JC, Newton CL, Pellicore JM, Young M, Lewis SD, Lucas
BJ, Krueger JA, McMasters DR, Yan Y, Kuo LC, Vacca JP, Selnick HG. Design
and synthesis of potent and selective macrocyclic thrombin inhibitors. Bioorg
Med Chem Lett.13, 2781-2784 (2003).
Structure – Student4
Design – Student3
Marinelli L, Gottschalk KE, Meyer A, Novellino E, Kessler H. Human Integrin
. J. Med. Chem. 47, 4166-4177
(2004).
8. March 3
Structure- Student6
Design – Student5
BSCI 275B 2005 - Syllabus
Enyedy IJ, Ling Y, Nacro K, Tomita Y, Wu X, Cao Y, Guo R, Li B, Zhu X,
Huang Y, Long YQ, Roller PP, Yang D, Wang S. Discovery of small-molecule
inhibitors of Bcl-2 through structure-based computer screening. J. Med. Chem.
44, 4313–4324 (2001).
March 10 Spring Break
9. March 17 Structure – Student8
Design – Student7
Doman TN, McGovern SL, Witherbee BJ, Kasten TP, Kurumbail R, Stallings
WC, Connolly DT, Shoichet BK. Molecular docking and high-throughput
screening for novel inhibitors of protein tyrosine phosphatase-1B. J. Med. Chem.
45, 2213–2221 (2002).
10. March 24 Structure – Student10
Design – Student9
Brenk R, Naerum L, Gradler U, Gerber HD, Garcia GA, Reuter K, Stubbs MT,
Klebe G. Virtual screening for submicromolar leads of tRNA-guanine
transglycosylase based on a new unexpected binding mode detected by crystal
structure analysis. J. Med. Chem. 46, 1133–1143 (2003).
11. March 31 Structure – Student12
Design – Student11
McNally VA, Gbaj A, Douglas KT, Stratford IJ, Jaffar M, Freeman S, Bryce RA.
Identification of a novel class of inhibitor of human and Escherichia coli
thymidine phosphorylase by in silico screening. Bio. Med. Chem. Lett. 13, 3705–
3709 (2003).
12. April 7
Structure – Student14
Design - Student13
Peng H, Huang N, Qi J, Xie P, Xu C, Wang J, Yang C. Identification of novel
inhibitors of BCR-ABL tyrosine kinase via virtual screening. Bioorg. Med. Chem.
Lett. 13, 3693–3699 (2003).
13. April 14 (ENC)
14. April 21. Recommendation of papers for the next year class.
Prepare two suggestions, and 1 min. argument in their favor that you can
pronounce in class.