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A possible explanation for a side-effect of a drug already on the market
A possible repositioning of a drug to treat a completely different condition
The reason a drug failed
A multi-target strategy to attack a pathogen
Exploiting the Structural Proteome 01/17/12 SPPS273
Need to Start with a 3D Drug-Receptor Complex - The PDB Contains Many Examples Exploiting the Structural Proteome 01/17/12 SPPS273 Generic Name Other Name Treatment PDBid Lipitor Atorvastatin High cholesterol 1HWK, 1HW8… Testosterone Testosterone Osteoporosis 1AFS, 1I9J .. Taxol Paclitaxel Cancer 1JFF, 2HXF, 2HXH Viagra Sildenafil citrate ED, pulmonary arterial hypertension 1TBF, 1UDT, 1XOS.. Digoxin Lanoxin Congestive heart failure 1IGJ
A Reverse Engineering Approach to Drug Discovery Across Gene Families Characterize ligand binding site of primary target (Geometric Potential) Identify off-targets by ligand binding site similarity (Sequence order independent profile-profile alignment) Extract known drugs or inhibitors of the primary and/or off-targets Search for similar small molecules Dock molecules to both primary and off-targets Statistics analysis of docking score correlations … Exploiting the Structural Proteome 01/17/12 SPPS273 Xie and Bourne 2009 Bioinformatics 25(12) 305-312
S-adenosylmethionine (SAM)-binding domain of SAM-dependent methyltransferases
Catechol- O -methyl transferase (COMT) is SAM-dependent methyltransferase
Entacapone and tolcapone are used as COMT inhibitors in Parkinson ’s disease treatment
Further investigation of NAD-binding proteins may uncover a potential new drug target for entacapone and tolcapone
Kinnings et al. 2009 PLoS Comp Biol 5(7) e1000423 Example 1 – Repositioning The TB Story 01/17/12 SPPS273
Functional Site Similarity between COMT and InhA
Entacapone and tolcapone docked onto 215 NAD-binding proteins from different species
M.tuberculosis Enoyl-acyl carrier protein reductase ENR (InhA) discovered as potential new drug target
InhA is the primary target of many existing anti-TB drugs but all are very toxic
InhA catalyses the final, rate-determining step in the fatty acid elongation cycle
Alignment of the COMT and InhA binding sites revealed similarities ...
Repositioning - The TB Story Kinnings et al. 2009 PLoS Comp Biol 5(7) e1000423 01/17/12 SPPS273
Binding Site Similarity between COMT and InhA Kinnings et al. 2009 PLoS Comp Biol 5(7) e1000423 Example 1 – Repositioning The TB Story 01/17/12 SPPS273 COMT SAM (cofactor) BIE (inhibitor) NAD (cofactor) InhA 641 (inhibitor)
L. Xie, L. Xie, S.L. Kinnings and P.E. Bourne 2012 Novel Computational Approaches to Polypharmacology as a Means to Define Responses to Individual Drugs, Annual Review of Pharmacology and Toxicology 52 : 361-379 [ PDF].