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Structural Isosteres of Phosphate Groups in the Protein Data Bank - ACS DC 2017

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In this work, we developed a computational workflow to mine the Protein Data Bank for isosteric replacements that exist in different binding site environments but have not necessarily been identified and exploited in compound design. Taking phosphate groups as examples, the workflow was used to construct 157 data sets, each composed of a reference protein complexed with AMP, ADP, ATP, or pyrophosphate as well other ligands. Phosphate binding sites appear to have a high hydration content and large size, resulting in U-shaped bioactive conformations recurrently found across unrelated protein families. A total of 16 413 replacements were extracted, filtered for a significant structural overlap on phosphate groups, and sorted according to their SMILES codes, see workflow in Figure 1. In addition to classical isosteres of phosphate, we found unexpected types of replacements that do not conserve charge or polarity, for example phosphate replaced by aliphatic groups, phenyl, or carbamoyl groups. The structural mechanism involved in structural isosteres appears varied: New interactions may be created, water molecules are important, in some case ion plays a role, and of course large and small conformational changes do occur at the binding sites. This study has implications both in the field of medicinal chemistry, i.e. it expands our knowledge of structural isosteres, and in the field of chemoinformatics, since our results have implications with respect to the definitions of chemical similarity.

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Structural Isosteres of Phosphate Groups in the Protein Data Bank - ACS DC 2017

  1. 1. 1254th American Chemical Society National Meeting08-2017 Structural isosteres of phosphate groups in the protein data bank Alexandre Borrel, PhD Postdoctoral Research Associate, Department of Chemistry, Bioinformatics Research Center, North Carolina State University, USA Division of pharmaceutical chemistry and technology Faculty of pharmacy University of Helsinki @AlBorrel
  2. 2. 2254th American Chemical Society National Meeting08-2017 Background: Drug optimization Hann, M.M. (2011). Medchemcomm 2: 349–355. Modify a drug to influence Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) properties in preserving an initial biological activity.Initial hit Final drug
  3. 3. 3254th American Chemical Society National Meeting08-2017 Definitions (1) Brown, N. (2014). Mol. Inform. 33: 458–462. Isostere or isosteric replacement (1): • Preserve biological activity • Retain the physicochemical or topological properties of the reference compound Carcinogen Analgesic Anti-inflammatory Cheminformatics to propose possible replacement
  4. 4. 4254th American Chemical Society National Meeting08-2017 In silico approaches Propose large databases of bioisosters, ligand based and structure based sc-PDB-frag (1): - Structure based - Interaction fingerprints KRIPO (2): - Structure based - Pharmacophore fingerprints SwissBioisostere (3): - Ligand based - Molecular pair from CHEMBL Hydrophobic H-bond (1) Desaphy J, Rognan D (2014) J Chem Inf Model 54:1908–1918. doi: 10.1021/ci500282c (2) Wood DJ, Vlieg J De, Wagener M, Ritschel T (2012) J Chem Inf Model 52:2031–2043. doi: 10.1021/ci3000776 (3) Wirth M, Zoete V, Michielin O, Sauer WHB (2013). Nucleic Acids Res 41:1137–1143. doi: 10.1093/nar/gks1059
  5. 5. 5254th American Chemical Society National Meeting08-2017 Local structural replacements Chemical groups which occupy the same space in two homologous superimposed complexes. Local structural replacement (LSR) Superimposed homologous proteins
  6. 6. 6254th American Chemical Society National Meeting08-2017 Study case: phosphate • Attractive target for therapeutic development (1) • 30% of the cellular proteins are phosphoproteins, 2,940 of structures available in PDB • Phosphate group is charged at biological pH, poorly permeable (2) Phosphate groups in ATP (1) Cohen, P. (2000). Trends Biochem. Sci. 25: 596–601. (2) Smith, F.W., Mudge, S.R., Rae, A.L., and Glassop, D. (2003). Plant Soil 248: 71–83.
  7. 7. 7254th American Chemical Society National Meeting08-2017 Computational workflow Extract from PDB (130,000 structures) complexed protein which included ligand with a phosphate group
  8. 8. 8254th American Chemical Society National Meeting08-2017 Computational workflow Filter the PDB (1,186 structures)
  9. 9. 9254th American Chemical Society National Meeting08-2017 Computational workflow Homologous protein (Blastp cutoff 10-100) 10,991 structures
  10. 10. 10254th American Chemical Society National Meeting08-2017 Computational workflow LSR
  11. 11. 11254th American Chemical Society National Meeting08-2017 Computational workflow 15,819 phosphate replacements
  12. 12. 12254th American Chemical Society National Meeting08-2017 Hierarchical organization Replacement containing (cycle, P, B, ….)
  13. 13. 13254th American Chemical Society National Meeting08-2017 Hierarchical organization Replacement containing (cycle, P, B, ….) • 16 Protein family, PDB information (KS = Kinase) • 70 clusters (30% of identity sequences) KS-5_4I3Z (Kinase – cluster 5 – PDB ID: 4I3Z) Replacement containing (cycle, P, B, ….)
  14. 14. 14254th American Chemical Society National Meeting08-2017 Hierarchical organization Replacement containing (cycle, P, B, ….) Replacement containing (cycle, P, B, ….) • LGD (Ligand) • LSR (Local Structural Replacements) • BS (Binding site, d = 4.5 Å) • 16 Protein family, PDB information (KS = Kinase) • 70 clusters (30% of identity sequences)
  15. 15. 15254th American Chemical Society National Meeting08-2017 Clustering navigation
  16. 16. 16254th American Chemical Society National Meeting08-2017 Isosteres? Number of atom similar - different LigandID–PDBIDIC50 Extract affinity information (from congener series)
  17. 17. 17254th American Chemical Society National Meeting08-2017 U-shape configuration U-shape replacements, found in different protein families (binding affinity decreases).
  18. 18. 18254th American Chemical Society National Meeting08-2017 Miscellaneous replacements Hydrophobic and positively charged replacements open perspectives to find not suspected before. Hydrophobic replacements NAD+ truncated (positive)
  19. 19. 19254th American Chemical Society National Meeting08-2017 Conclusion • 15,819 phosphate replacements • Organization based on target and type of structural replacements • Mechanisms for phosphate replacements (protein or metal displacement) • New no suspected replacement (U-shape, hydrophobic, or positively charged) • Workflow is fully customizable (github) Zhang, Y.*, Borrel, A.*, Ghemtio, L., Regad, L., Boije af Gennäs, G., Camproux, A.-C., et al. (2017). Structural Isosteres of Phosphate Groups in the Protein Data Bank. J. Chem. Inf. Model. 57: 499–516.
  20. 20. 20254th American Chemical Society National Meeting08-2017 Acknowledgments Authors: - Yuezhou Zhang - Leo Ghemtio - Leslie Regad - Gustav Boije af Gennäs - Anne-Claude Camproux - Jari Yli-Kauhaluoma - Henri Xhaard* Fourches’ lab
  21. 21. 21254th American Chemical Society National Meeting08-2017
  22. 22. 22254th American Chemical Society National Meeting08-2017 Water molecules versus RX • Poorly crystallized • Present only at very high resolution (< 1.5 Å) Datasets from the PDB with 1.5 Å and 3 Å of resolution
  23. 23. 23254th American Chemical Society National Meeting08-2017 Miscellaneous replacements Hydrophobic replacements, favour hydrophobic contacts in binding site. Positively charged replacement is surprising considering that the phosphate groups are negatively charged.
  24. 24. 24254th American Chemical Society National Meeting08-2017 Bioisoster replacement “One of two or more substances related to each other by origin, structure, or function.” (IUPAC) Shin, Y., Chen, W., Habel, J., Duckett, D., Ling, Y.Y., Koenig, M., et al. (2009). Bioorganic Med. Chem. Lett. 19: 3344–3347. A group change and the affinity (IC50)
  25. 25. 25254th American Chemical Society National Meeting08-2017 Hierarchical organization Dependency of protein target: LSR target based classification Meanwell, N.A.N.N. a (2011). J. Med. Chem. 54: 2529–2591. cPLAA2α inhibitor analogs + + + - - - Angiotensin II receptor antagonist analogs
  26. 26. 26254th American Chemical Society National Meeting08-2017 Structural replacement ESP: electrostatic score potential (1) = 1: phosphate is fully covert by the LSR LSR superimposition not overlap completely with phosphate groups
  27. 27. 27254th American Chemical Society National Meeting08-2017 Replacement mechanisms PDB code: 3JZI – 1DV2
  28. 28. 28254th American Chemical Society National Meeting08-2017 Replacement mechanisms PDB code: 3JZI – 1DV2
  29. 29. 29254th American Chemical Society National Meeting08-2017 Replacement mechanisms PDB code: 3JZI – 1DV2 Protein replaces the phosphate group
  30. 30. 30254th American Chemical Society National Meeting08-2017 Chemical replacement Southall, N.T., and Ajay (2006). J. Med. Chem. 49: 2103–2109 Example of chemical replacements in kinase patent space from gefitinib remove Replaceadd

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