1. The document discusses using databases like the Protein Data Bank (PDB) to better understand protein receptors and target recognition through data mining and analyzing protein structures and interactions. 2. It describes research tools for discovering and characterizing protein receptors, and how they can be used to undertake high-throughput hypothesis generation for protein-drug interactions on a proteome-wide scale. 3. The analysis of the Mycobacterium tuberculosis proteome and identification of potential drug targets from existing drugs is provided as an example of this approach.

1. Mining databases for understanding target recognition Philip E. Bourne 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

2. Mining databases for understanding target recognition – well the PDB anyway Philip E. Bourne 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

3. “ If you remember 3 things from a lecture a week later it was a good lecture” from Ten Simple Rules for Making Good Oral Presentations PLoS Comp Biol 2007 3(4): e77 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

4. 1. The PDB services almost 200,000 scientists per month, but you are special – take advantage of this offer 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

5. “ I want to review all multimeric quaternary complexes in the PDB that may be of interest in the understanding of allosteric mechanisms exhibited by such complexes” Jean-Pierre Changeux

6. 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

8. Identify biological relatedness even if quaternary structures show variability

10. Our scores allow to pick out unusual ones: 1Y01 Z-score: 6.23 Coverage 1:22 Coverage 2:59 TM-Score: 0.56 4HHB (self) Z-score: 8.49 Coverage 1:100 Coverage 2:100 TM-Score: 1.0 2W72 Distal site hemoglobin mutant AHSP bound to Fe(II) alpha-hemoglobin Z-score: 7.02 Coverage 1:76 Coverage 2:100 TM-Score: 0.98

12. 2. We have research tools, not part of the PDB (yet), which are important for discovering and characterizing protein receptors 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

16. 3. We can undertake high-throughput hypothesis generation for protein-drug interactions on a proteome-wide scale 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

20. Map 2 onto 1 – The TB-Drugome http://funsite.sdsc.edu/drugome/TB/ Similarities between the binding sites of M.tb proteins (blue), and binding sites containing approved drugs (red).

22. Top 5 Most Highly Connected Drugs 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action Drug Intended targets Indications No. of connections TB proteins levothyroxine transthyretin, thyroid hormone receptor α & β -1, thyroxine-binding globulin, mu-crystallin homolog, serum albumin hypothyroidism, goiter, chronic lymphocytic thyroiditis, myxedema coma, stupor 14 adenylyl cyclase, argR , bioD, CRP/FNR trans. reg ., ethR , glbN , glbO, kasB , lrpA , nusA , prrA , secA1 , thyX , trans. reg. protein alitretinoin retinoic acid receptor RXR- α , β & γ , retinoic acid receptor α , β & γ -1&2, cellular retinoic acid-binding protein 1&2 cutaneous lesions in patients with Kaposi's sarcoma 13 adenylyl cyclase, aroG , bioD, bpoC, CRP/FNR trans. reg. , cyp125 , embR , glbN , inhA , lppX , nusA , pknE , purN conjugated estrogens estrogen receptor menopausal vasomotor symptoms, osteoporosis, hypoestrogenism, primary ovarian failure 10 acetylglutamate kinase, adenylyl cyclase, bphD , CRP/FNR trans. reg. , cyp121 , cysM, inhA , mscL , pknB , sigC methotrexate dihydrofolate reductase, serum albumin gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, severe psoriasis, rheumatoid arthritis 10 acetylglutamate kinase, aroF , cmaA2 , CRP/FNR trans. reg. , cyp121 , cyp51 , lpd , mmaA4 , panC , usp raloxifene estrogen receptor, estrogen receptor β osteoporosis in post-menopausal women 9 adenylyl cyclase, CRP/FNR trans. reg., deoD, inhA, pknB , pknE , Rv1347c , secA1, sigC

23. Acknowledgements Funding Agencies: NSF, NIGMS, DOE, NLM, NCI, NCRR, NIBIB, NINDS, NIDDK 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action