1. CS 790 – Bioinformatics Introduction and overview

2. CS 790 – BioinformaticsCourse Overview2 What is Bioinformatics? DNA (and RNA)Proteins

3. CS 790 – BioinformaticsCourse Overview3 What is Bioinformatics? Computational Biology Bioinformatics Genomics Proteomics Functional genomics Structural bioinformatics

4. CS 790 – BioinformaticsCourse Overview4 Why is Bioinformatics Important?  Applications areas include Medicine Pharmaceutical drug design Toxicology Molecular evolution Biosensors Biomaterials Biological computing models DNA computing

5. CS 790 – BioinformaticsCourse Overview5 The Role of Computational Biology Source: GenBank 3D Structures Growth: Source: http://www.rcsb.org/pdb/ holdings.html GenBank BASEPAIR GROWTH

6. CS 790 – BioinformaticsCourse Overview6 Fighting Human Disease  Genetic / Inherited Diabetes  Viral Flu, common cold  Bacterial Meningitis, Strep throat

7. Drug Development Life Cycle Years 0 2 4 6 8 10 12 14 16 Discovery (2 to 10 Years) Preclinical Testing (Lab and Animal Testing) Phase I (20-30 Healthy Volunteers used to check for safety and dosage) Phase II (100-300 Patient Volunteers used to check for efficacy and side effects) Phase III (1000-5000 Patient Volunteers used to monitor reactions to long-term drug use) FDA Review & Approval Post-Marketing Testing $600-700 Million! 7 – 15 Years!

8. CS 790 – BioinformaticsCourse Overview8 Drug lead screening 5,000 to 10,000 compounds screened 250 Lead Candidates in Preclinical Testing 5 Drug Candidates enter Clinical Testing; 80% Pass Phase I One drug approved by the FDA 30%Pass Phase II 80% Pass Phase III

9. CS 790 – BioinformaticsCourse Overview9 What are we going to learn?  DNA, Proteins, life, and disease: an overview  Basic chemistry introduction/review  Basic biochemistry: proteins  Basic biochemistry: DNA, genes, and molecular evolution (Dr. Dan Krane, Biological Sciences)  Drug docking and screening, dealing with water molecules: Dr. Raymer  Student presentations: techniques in bioinformatics

10. CS 790 – BioinformaticsCourse Overview10 Student Presentations  Students will each make 1 or 2 one-hour presentations on topics in bioinformatics Tutorial Survey Research Paper  Each class, we’ll turn in either: A one-page summary of the previous presentation, or A mini-project assigned as part of the presentation.  We’ll talk more about this next time  Web page

11. CS 790 – BioinformaticsCourse Overview11 DNA is the blueprint for life  Every cell in your body has 23 chromosomes in the nucleus  The genes in these chromosomes determine all of your physical attributes. Image source: Crane digital, http://www.cranedigital.com/

12. CS 790 – BioinformaticsCourse Overview12 Mapping the Genome  The human genome project has provided us with a draft of the entire human genome. Four bases: A, T, C, G 3.12 billion base- pairs 99% of these are the same Polymorphisms = where they differ

13. CS 790 – BioinformaticsCourse Overview13 How does the code work?  Template for construction of proteins

14. CS 790 – BioinformaticsCourse Overview14 Proteins: Molecular machinery  Proteins in your muscles allows you to move: myosin and actin

15. CS 790 – BioinformaticsCourse Overview15 Proteins: Molecular machinery  Enzymes (digestion, catalysis)  Structure (collagen)

16. CS 790 – BioinformaticsCourse Overview16 Proteins: Molecular machinery  Signaling (hormones, kinases)  Transport (energy, oxygen) Image source: Crane digital, http://www.cranedigital.com/

17. CS 790 – BioinformaticsCourse Overview17 Example Case: HIV Protease 1.Exposure & infection 2.HIV enters your cell 3.Your own cell reads the HIV “code” and creates the HIV proteins. 4.New viral proteins prepare HIV for infection of other cells. http://whyfiles.org/035aids/index.html © George Eade, Eade Creative Services, Inc.

18. CS 790 – BioinformaticsCourse Overview18 HIV Protease & Inhibition

19. CS 790 – BioinformaticsCourse Overview19 HIV Protease as a drug target  Many drugs bind to protein active sites.  This HIV protease can no longer prepare HIV proteins for infection, because an inhibitor is already bound in its active site. HIV Protease + Peptidyl inhibitor (1A8G.PDB)

20. CS 790 – BioinformaticsCourse Overview20 Drug Discovery  Target Identification What protein can we attack to stop the disease from progressing?  Lead discovery & optimization What sort of molecule will bind to this protein?  Toxicology Does it kill the patient? Does it have side effects? Does it get to the problem spots?

21. CS 790 – BioinformaticsCourse Overview21 Drug discovery: past & present  Put some of the infectious agent into thousands of tiny wells  Add a known drug lead compound into each well. Try nearly every drug lead known.  See which ones kill the agent… To small to see, so we have to use chemical tests called assays

22. CS 790 – BioinformaticsCourse Overview22 Finding drug leads  Once we have a target, how do we find some compounds that might bind to it?  The old way: exhaustive screening  The new way: computational screening!

23. CS 790 – BioinformaticsCourse Overview23 Drug Lead Screening & Docking  Complementarity Shape Chemical Electrostatic ? ?

24. CS 790 – BioinformaticsCourse Overview24 Problems in Bioinformatcs  Genomics Gene finding Annotation  Sequence alignment and database search Functional genomics  Microarray expression, “gene chips”  Proteomics Structure prediction  Comparative modeling Function prediction  Structural bioinformatics Molecular docking, screening, etc.