1. LSM3241: Bioinformatics and Biocomputing Lecture 2: Bioinformatics of viral genome Prof. Chen Yu Zong Tel: 6874-6877 Email: csccyz@nus.edu.sg http://xin.cz3.nus.edu.sg Room 07-24, level 7, SOC1, National University of Singapore csccyz@nus.edu.sg http://xin.cz3.nus.edu.sgcsccyz@nus.edu.sg http://xin.cz3.nus.edu.sg

2. 2 Resource of Viral Genomes NCBI Genome Database http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome

3. 3 Resource of Viral Genomes NCBI Genome Database http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome 2,226 entries of viral genomes (1,524 distinct virus strains) in the database. Early 2005 figure: 1,250 entries and 1,022 distinct 1,193 entries of complete viral genome. Early 2005 figure: 900

4. 4 Resource of Viral Genomes NCBI Genome Database http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome 12 entries of coronavirus genomes (8 in early 2005) 16 entries of influenza H5N1 genomes

5. 5 Resource of Viral Genomes NCBI Genome Database http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome Information of viral genomes in the database can also be retrieved by clicking the viruses link: Click Here

6. 6 Resource of Viral Genomes NCBI Genome Database http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome List of viral genomes: (1,927 entries in Jan 2006, 1,461 in Jan 2005)

7. 7 Resource of Viral Genomes NCBI Genome Database http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome Viral taxonomy groups:

8. 8 Resource of Viral Genomes NCBI Genome Database http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=Search&DB=genome Viral genome list:

9. 9 Resource of Viral Genomes Viral genome list:

10. 10 Bioinformatics of Viral Genomes Viral name link: Viral genome link All entries

11. 11 Bioinformatics of Viral Genomes Viral protein link: Limit to title search

12. 12 Bioinformatics of Viral Genomes SARS coronavirus PP1ab PID link. It gives multiple entries from difference strains or from related species Viral strain

13. 13 Different strains of SARS coronavirus

14. 14 Bioinformatics of Viral Genomes Note: Viral polyprotein is not a single protein, it is a combination of several proteins. Information about these proteins can be difficult to read Suggestion: Looking into a latest NCBI entry of the same virus from a reputable research group

15. 15 Bioinformatics of Viral Genomes SARS coronavirus unknown sars3a PID link:

16. 16 Bioinformatics of Viral Genomes Alternative way to find SARS coronavirus genome. Look for the latest entry with complete genome and good functional annotation. Not all entries have these.

17. 17 Bioinformatics of Viral Genomes The latest good entry: AY572038 civet020 SARS coronavirus (In Jan 2005 AY310120 SARS coronavirus FRA), complete genome

18. 18 SARS Coronavirus Genome You are expected to find the info about each gene (genome location, sequence, function)

19. 19 Function of SARS Coronavirus Genes

20. 20 Bioinformatics of Viral Genomes Where to find the proteins in the genome entry? Source 1: mat_peptide Protein name

21. 21 Bioinformatics of Viral Genomes Where to find the proteins in the genome entry? Source 1: mat_peptide

22. 22 Bioinformatics of Viral Genomes Where to find the proteins in the genome entry? Putative 3C-like protease mat_peptide link: Protein name Protein function

23. 23 Bioinformatics of Viral Genomes Where to find the proteins in the genome entry? Source 2: CDS Protein name

24. 24 Bioinformatics of Viral Genomes Where to find the proteins in the genome entry? Source 2: CDS

25. 25 Bioinformatics of Viral Genomes Where to find the proteins in the genome entry? Source 2: CDS

26. 26 Bioinformatics of Viral Genomes Where to find the proteins in the genome entry? Source 2: CDS

27. 27 Bioinformatics of Viral Genomes Where to find the proteins in the genome entry? Nucleocapsid protein protein_id link: Protein name

28. 28 Bioinformatics of Viral Genomes How to find the name or function of a putative protein in a genome? Medline keyword search Google search

29. 29 Bioinformatics of Viral Genomes What if the function of a putative protein is unknown? Sequence alignment (BLAST, PSI-BLAST). This will be further discussed in lecture 4. Motif analysis (Conduct a PROSITE motif search)PROSITE If sequence analysis fails or in doubt, try machine learning method (SVMProt, Nucleic Acids Res., 31: 3692-3697; ProtFun, Bioinformatics, 19:635-642). This will be studied in lecture 5.SVMProt ProtFun

30. 30 Bioinformatics of Viral Genomes Drug design: Step 1: Finding the right target in the genome A key protein involved in viral cycle (stop the disease process) Different from human proteins (reduce side-effects) Step 2: Finding or making a chemical agent to stop the protein In majority of cases: protein inhibitors Step 3: Test and clinical trials

31. 31 Bioinformatics of Viral Genomes SARS Drug design: The target: 3C like protease

32. 32 Bioinformatics of Viral Genomes SARS Drug design: Inhibitor design: Finding inhibitors of similar proteins, such as those of the same name (3C like proteases or 3C proteases of other species), may offer clues to inhibitor design. Search from NCBINCBI

33. 33 Bioinformatics of Viral Genomes Search from NCBI finds 19 references.NCBI

34. 34 Bioinformatics of Viral Genomes Check each abstract to find the name of one or more inhibitors. Be prepared to read the full paper to find inhibitors

35. 35 Bioinformatics of Viral Genomes Make sure the paper talks about the inhibitors of the right protein. This one actually talks about inhibitors of protease family, thus may not necessarily be suitable for SARS 3C like protease

36. 36 Bioinformatics of Viral Genomes SARS Drug design: Inhibitor design: Finding inhibitors of similar proteins, such as those of the same name (3C like proteases or 3C proteases of other species), may offer clues to inhibitor design. Search from GoogleGoogle

37. 37 Bioinformatics of Viral Genomes Search from Google finds numerous entriesGoogle

38. 38 Bioinformatics of Viral Genomes Check each entry to find the name of one or more inhibitors. Be prepared to read the full paper to find inhibitors

39. 39 Bioinformatics of Viral Genomes Design of SARS 3C like protease inhibitors using rhinovirus 3C like protease inhibitors as templates

40. 40 Summary of Today’s lecture Genome database at NCBI Viral genomes –SARS coronavirus genome as an example Finding proteins from a genome Therapeutic target identification from a genome and inhibitor design