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SubCav - Tool for subpocket comparison and alignment

Kalliokoski T, Olsson TSG, Vulpetti A. J. Chem. Inf. Model. 2013 , 53, 131-141. SubCav - Tool for subpocket comparison and alignment. Dr. Tuomo Kalliokoski Lead Discovery Center GmbH, Dortmund, Germany. Work conducted at Novartis Institutes for Biomedical Research, Basel, Switzerland.

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SubCav - Tool for subpocket comparison and alignment

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  1. Kalliokoski T, Olsson TSG, Vulpetti A. J. Chem. Inf. Model. 2013, 53, 131-141. SubCav - Tool for subpocketcomparison and alignment Dr. Tuomo Kalliokoski Lead Discovery Center GmbH, Dortmund, Germany Work conducted at Novartis Institutes for Biomedical Research, Basel, Switzerland

  2. Protein Databank (PDB) is growing • Number of searchable structures 1972-Mar 2013

  3. How many fragments are there? 8 million unique chemical structures 2 million lead-like structures 400,000 Rule-Of-Three compliant structures Zueggand Cooper. Drug-Likeness and Increased Hydrophobicity of Commercially Available Compound Libraries for Drug Screening. Curr Top Med Chem2012, 12, 1500-1513.

  4. Bridging “Structural”-Space and “Fragment”-Space Fragment chemical space is too large for experimental Fragment-Based Drug Design (FBDD) The information content of PDB is increasing The need to develop tools for FBDD to take advantage of PDB!

  5. Binding site similarity “The availability of such data provides a basis for the identification of bioisosteres that are target specific. The resulting bioisosteres might be expected to provide more reliable information when modifying an existing lead compound than do existing approaches, which are based either on empirical measures of inter-substituent similarity or on non-target specific crystallographic data.” Kennewell EA, Willett P, Ducrot P, Luttmann C. Identification of target-specific bioisosteric fragments from ligand–protein crystallographic data. J Comput Aided Mol Des 2006, 20, 385-394.

  6. Subpockets and fragments BRICS* *DegenJ, Wegscheid-Gerlach C, Zaliani A, Rarey M. On the art of compiling and using ’drug-like’ chemical fragment spaces. ChemMedChem2008, 3, 1503–1507.

  7. SubCav • Tool for subpocket similarity searching and alignment • Based on pharmacophoric fingerprints with geometric hashing-inspired alignment • Source code available via anna.vulpetti@novartis.com

  8. Fingerprint descriptor CA 9.3Å=4 D= 6.0Å=2 3.4Å=1 A=

  9. Alignment algorithm

  10. Implementation details

  11. Validation study • Align pairwise all similar subpockets in PSMDB* (non-redundant subset of PDB) • 3,268,620 pairs from 3,886 PDBs with 17,044 subpocketswith 332 different fragments • Two alignment methods: • Fragment-based alignment • SubCav-based alignment * Wallach I, Lilien R. The Protein–Small-Molecule Database (PSMDB), A Non-Redundant Structural Resource for the Analysis of Protein-Ligand Binding, Bioinformatics2009, 25, 615-620.

  12. When are two subpockets similar? • Two subpockets are similar if both after alignment have • Root-Median-Square-Deviation (RMSD) of fragments found in subpocketsis less than 1.5 Å • Enough matched features* RMSD = 1.00 Overlap = 0.79 *Matched feature=if two features from the two subpockets are within 1 Å distance

  13. Very rarely subpockets with same fragments are geometrically similar...

  14. SubCav finds 73%-85% of fragment-based (plus something else!)

  15. Three structures of thrombin aligned. The query (magenta) fragment-aligned (green) vs. SubCav aligned (cyan)

  16. Bioisosteric replacement example ACP Heat Shock Protein 90 (HSP 90)

  17. Bioisosteric replacement example Escherichia coli DNA gyraseB (sequencesimilarity 30%)

  18. Bioisosteric replacement example Adenine -> pyrazole? Escherichia coli DNA gyraseB (sequencesimilarity 30%)

  19. Bioisosteric replacement example HSP90 inhibitor

  20. Analysis of Histone Methyl-Transferase Binding Sites S-adenosylmethionine (SAM) or S-adenosyl-l-homocysteine (SAH) Fragmented in three: adenine, ribose, and tailfragments Pairwise SubCav-alignment and hierarchical clustering based on Overlap

  21. Analysis of Histone Methyl-Transferase Binding Sites The clustering of the cofactor binding site by subpockets around each specific fragment revealed different levels of local similarity within the selected proteins set.

  22. Analysis of Histone Methyl-Transferase Binding Sites The clustering of the cofactor binding site by subpockets around each specific fragment revealed different levels of local similarity within the selected proteins set.

  23. Analysis of Histone Methyl-Transferase Binding Sites C B A D

  24. Take home message Subpocket analysis can provide ideas in CADD

  25. Acknowledgements • Novartis Institutes for Biomedical Research: • Dr. Anna Vulpetti (mentor & co-author) • Education office (Presidential Postdoctoral Fellowship) • Cambridge Crystallographic Data Centre: • Dr. Tjelvar Olsson (mentor & co-author) • Chemical Computing Group: • Dr. Guido Kirsten (idea for alignment protocol)

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