Workshop031211

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

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

“ 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

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

“ 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

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

Its not as easy as it sounds.. Group II Chaperonins - Open and Closed Conformation
all chains are sequence identical within one chaperone and 95% similar between the two PDB entries
3KFK 3KFB

Identify biological relatedness even if quaternary structures show variability

Methodology
Take all chains from a PDB95 sequence cluster
Fetch the (1st) Biological Assembly (BA) for the PDB ID of the chain
Align the whole BAs against each other using CE-CP
Prlic et al 2010 Bioinformatics 10.1093/bioinformatics/btq572

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

Long Term Goal
Characterize all quaternary structures found in the PDB according to level of structural similarity
Where structural similarity exists classify according to ligands bound
Characterize those with drug binding sites at the subunit boundaries
Better characterize allosteric mechanisms associated with quaternary structures
03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

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

Initially assign C  atom with a value that is the distance to the environmental boundary
Update the value with those of surrounding C  atoms dependent on distances and orientation – atoms within a 10A radius define i
Conceptually similar to hydrophobicity
or electrostatic potential that is
dependant on both global and local
environments
Characterization of the Ligand Binding Site - The Geometric Potential Xie and Bourne 2007 BMC Bioinformatics, 8(Suppl 4):S9

Discrimination Power of the Geometric Potential
Geometric potential can distinguish binding and non-binding sites
100 0 Geometric Potential Scale Xie and Bourne 2007 BMC Bioinformatics, 8(Suppl 4):S9

Search for Similar Ligand Binding Sites L E R V K D L L E R V K D L Structure A Structure B
Build an associated graph from the graph representations of two structures being compared. Each of the nodes is assigned with a weight from the similarity matrix
The maximum-weight clique corresponds to the optimum alignment of the two structures
Xie and Bourne 2008 PNAS , 105(14) 5441 http://funsite.sdsc.edu

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

The TB-Drugome
Determine the TB structural proteome
Determine all known drug binding sites from the PDB
Determine which of the sites found in 2 exist in 1
Call the result the TB-drugome
Kinnings et al 2010 PLoS Comp Biol 6(11): e1000976 Workshop in Allosteric and Orthosteric Ligands in Drug Action 03/12/11

1. Determine the TB Structural Proteome
High quality homology models from ModBase (http://modbase.compbio.ucsf.edu) increase structural coverage from 7.1% to 43.3%
284 1, 446 3, 996 2, 266 TB proteome homology models solved structures 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

2. Determine all Known Drug Binding Sites in the PDB
Searched the PDB for protein crystal structures bound with FDA-approved drugs
268 drugs bound in a total of 931 binding sites
No. of drug binding sites Methotrexate Chenodiol Alitretinoin Conjugated estrogens Darunavir Acarbose 03/12/11 Workshop in Allosteric and Orthosteric Ligands in Drug Action

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).

From a Drug Repositioning Perspective
Similarities between drug binding sites and TB proteins are found for 61/268 drugs
41 of these drugs could potentially inhibit more than one TB protein
No. of potential TB targets raloxifene alitretinoin conjugated estrogens & methotrexate ritonavir testosterone levothyroxine chenodiol 03/12/11

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

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

Workshop031211

by Philip Bourne on Mar 12, 2011

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