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Evaluating Bioisosteric Replacements Taking the Whole Molecule into Account<br />Mark Mackey<br />
Current Versions<br />
Field Points<br />Condensed representation of electrostatic, hydrophobic and shape properties (“protein’s view”) <br />Mol...
+ve ionic<br />H-bond acceptor<br />Aromatic      p cloud ‘H acceptor’<br />-ve ionic<br />H-bond donor<br />Hydrophobes<b...
XEDs make Fields Work<br />Field patterns from Cresset’s proprietary XED force field reproduce experimental results<br />N...
Information Provided by Fields<br />Structure<br />Fields<br />Experimental<br />Field points give you new insights into y...
Comparing Molecules<br />Clique based initial alignment<br />Uses the distance matrix of Field Points<br />Detailed score<...
N-methyl acetamide<br />Imidazole<br />Field Alignment<br />
N-methyl acetamide<br />Imidazole<br />Field Scoring<br />To score a particular alignment, we use the field points of mole...
Field Scoring<br />N-methyl acetamide<br />Imidazole<br />To score a particular alignment, we use the field points of mole...
Bioisosteres – PDE III<br />Biologically relevant method for comparing molecules<br />Bioisosteres<br />Bioisosteric group...
FieldStere<br />Finding bioisosteres by replacing sections of the molecule<br />Valdecoxib<br />Etoricoxib<br />Rofecoxib<...
FieldStere’s Approach<br />Select a region to replace and remove these atoms<br />
FieldStere’s Approach<br />Select a region to replace and remove these atoms<br />Search database for matching fragments<b...
Select a region to replace and remove these atoms<br />Search database for matching fragments<br />(geometric search only)...
Select a region to replace and remove these atoms<br />Search database for matching fragments<br />(geometric search only)...
Produces more diverse, non-obvious bioisosteres<br />Avoids fragment scoring limitations<br />Allows for electronic influe...
Where do you get fragments from?<br />Fragment existing molecules<br />Fragment at<br />Heteroatoms<br />C=O and C=S<br />...
Creating Fragments<br />Conformation hunt done on all fragments<br />
Database of Replacement Moieties<br />Series of commercial compounds<br />fragmented and recombined<br />Resultant moietie...
Example - COX-2<br />Search for Bioisosteres for cyclic lactone of Rofecoxib<br />Search Common Dbs<br />Actives:<br />9 o...
COX-2 Results<br />
COX-2 Results<br />
Product Space<br />Result 1,484<br />Target<br />Result 5<br />
Cross Scoring<br />Separate target and reference for scoring<br />Bring in interactions from a parallel series<br />Multip...
Select a region to replace and remove these atoms<br />Search database for matching fragments<br />(geometric search only)...
Cross scoring example - BACE<br />Multiple known actives for BACE<br />Binding site has flexibility<br />Ligand based meth...
PDB 2IQG - Hydroxyethylamine based inhibitor<br />Complex chemistry<br />Chiral<br />PDB 3L59 - Small guanidine based inhi...
2IQG - Detail<br />
3L59 - Detail<br />
Can we use 3L59 to improve 2IQG ?<br />Use 2IQG as the “Target”<br />Score replacements against 3L59 - the “Reference”<br ...
Preliminary Results<br />Result 18<br />Result 31<br />Result 55<br />Result 83<br />Result 42<br />Result 110<br />
Cross Scoring 2 - Fragment Growing<br />FieldStere version 3.0.0 fragment growth example:<br />P38 kinase bound to a fragm...
Fragment in DFG-out pocket, PDB:3K3I <br />predominant hinge<br />conformation<br />
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Tim Cheeseright, Cresset, 'Introducing Fragment Growing in FieldStere and other cool stuff'

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The upcoming release of FieldStere will enable fragment growing, This presentation will introduce the current operation and results then focus on the new features that enable more complex bioisostere searching experiments.

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  • Notes:FieldStere uses a product centric approach, that is all potential bioisosteres are scored only as complete “product” molecules and not as isolated fragments. To create the products with suitable properties a multi-stage process is used.Once you have chosen the portion of the target molecule that you wish to replace, a copy of the target is created with these atoms removed. The geometric distance and angles between any broken bonds are recorded. FieldStere then searches a database for any fragment that has the right number of connection points that geometrically match the broken bonds in the target. Matches are considered on the basis of both angle and distance.
  • Notes:FieldStere uses a product centric approach, that is all potential bioisosteres are scored only as complete “product” molecules and not as isolated fragments. To create the products with suitable properties a multi-stage process is used.Once you have chosen the portion of the target molecule that you wish to replace, a copy of the target is created with these atoms removed. The geometric distance and angles between any broken bonds are recorded. FieldStere then searches a database for any fragment that has the right number of connection points that geometrically match the broken bonds in the target. Matches are considered on the basis of both angle and distance.
  • Notes:Fragments that have the correct angles and distances between connection points are merged into the target molecule to form the “product”. Only now, as a whole product molecule is this bioisosteric replacement scored against the starting structure for electrostatic and shape similarity.Using this product centric view generates a wider range of biologically relevant bioisosteres.
  • Notes:Fragments that have the correct angles and distances between connection points are merged into the target molecule to form the “product”. Only now, as a whole product molecule is this bioisosteric replacement scored against the starting structure for electrostatic and shape similarity.Using this product centric view generates a wider range of biologically relevant bioisosteres.
  • Notes:FieldStere’s product centric approach gives excellent results, producing a more diverse set of bioisosteres.The graphic shows an overlay of the thiazolotriazine (bottom right, grey carbons) with rofecoxib (green carbons). The Field pattern surrounding the retained portions of the molecule are highly conserved in these molecules (both are active), however, subtle changes can still be seen particularly near the sulfone group.
  • Notes:FieldStere’s database generator creates a database of potential bioisosteres by fragmenting whole molecules and then recombining the resulting small fragments into larger fragements. Whole molecules are fragmented at bonds to rings and bonds to heteroatoms. Recombination of small fragments is limited to producing moieties with MW &lt; 250 , NRB &lt; 5, 5 or less small fragments used.Once formed, the larger moieties are conformationally searched and the resulting conformations are stored in the database.
  • Notes:Fragments that have the correct angles and distances between connection points are merged into the target molecule to form the “product”. Only now, as a whole product molecule is this bioisosteric replacement scored against the starting structure for electrostatic and shape similarity.Using this product centric view generates a wider range of biologically relevant bioisosteres.
  • Transcript of "Tim Cheeseright, Cresset, 'Introducing Fragment Growing in FieldStere and other cool stuff'"

    1. 1. Evaluating Bioisosteric Replacements Taking the Whole Molecule into Account<br />Mark Mackey<br />
    2. 2. Current Versions<br />
    3. 3. Field Points<br />Condensed representation of electrostatic, hydrophobic and shape properties (“protein’s view”) <br />Molecular Field Extrema (“Field Points”)<br />= Positive <br />= Negative<br />= Shape<br />= Hydrophobic<br />3D Molecular Electrostatic Potential (MEP)<br />Field Points<br />2D<br />
    4. 4. +ve ionic<br />H-bond acceptor<br />Aromatic p cloud ‘H acceptor’<br />-ve ionic<br />H-bond donor<br />Hydrophobes<br />Aromatic in-plane ‘H donor’<br />“Stickiest” surfaces (high vdW)<br />Field points give you new insights into your molecule<br />Explanatory Power of Fields<br />= Positive <br />= Negative<br />= Shape<br />= Hydrophobic<br />Field point size show importance<br />
    5. 5. XEDs make Fields Work<br />Field patterns from Cresset’s proprietary XED force field reproduce experimental results<br />Not using XEDs<br />Interaction of Acetone and Any-OH from small molecule crystal structures<br />Experimental<br />Using XEDs<br />XED adds p-orbitals to get better representation of atoms<br />
    6. 6. Information Provided by Fields<br />Structure<br />Fields<br />Experimental<br />Field points give you new insights into your molecule<br />
    7. 7. Comparing Molecules<br />Clique based initial alignment<br />Uses the distance matrix of Field Points<br />Detailed score<br />Single point<br />Uses Field-Point on Field Scoring<br />Optional simplex based optimisation of alignment<br />Rigid body - no bonds twisted<br />Uses detailed score as optimisation parameter<br />
    8. 8. N-methyl acetamide<br />Imidazole<br />Field Alignment<br />
    9. 9. N-methyl acetamide<br />Imidazole<br />Field Scoring<br />To score a particular alignment, we use the field points of molecule 1 to sample the actual field of molecule 2<br />Cheeseright et al, J. Chem Inf. Mod., 2006, 665<br />
    10. 10. Field Scoring<br />N-methyl acetamide<br />Imidazole<br />To score a particular alignment, we use the field points of molecule 1 to sample the actual field of molecule 2 and vice-versa<br />Cheeseright et al, J. Chem Inf. Mod., 2006, 665<br />
    11. 11. Bioisosteres – PDE III<br />Biologically relevant method for comparing molecules<br />Bioisosteres<br />Bioisosteric groups<br />
    12. 12. FieldStere<br />Finding bioisosteres by replacing sections of the molecule<br />Valdecoxib<br />Etoricoxib<br />Rofecoxib<br />12nM<br />
    13. 13. FieldStere’s Approach<br />Select a region to replace and remove these atoms<br />
    14. 14. FieldStere’s Approach<br />Select a region to replace and remove these atoms<br />Search database for matching fragments<br />(geometric search only)<br />(search runs on fragment conformations)<br />
    15. 15. Select a region to replace and remove these atoms<br />Search database for matching fragments<br />(geometric search only)<br />(search runs on fragment conformations)<br />Form Products<br />(minimise and add Field Points)<br />FieldStere’s Approach<br />
    16. 16. Select a region to replace and remove these atoms<br />Search database for matching fragments<br />(geometric search only)<br />(search runs on fragment conformations)<br />Form Products<br />(minimise and add Field Points)<br />Score<br />FieldStere’s Approach<br />0.88<br />
    17. 17. Produces more diverse, non-obvious bioisosteres<br />Avoids fragment scoring limitations<br />Allows for electronic influence of replacing a moiety on the rest of the molecule and vice versa<br />Allows for neighbouring group effects<br />Whole-Molecule Scoring Advantages<br />
    18. 18. Where do you get fragments from?<br />Fragment existing molecules<br />Fragment at<br />Heteroatoms<br />C=O and C=S<br />Bonds to rings<br />Not NO2, COOH, etc<br />Generate all sets of connected pieces<br />Subject to MW, NH, and rotatable bond limits<br />
    19. 19. Creating Fragments<br />Conformation hunt done on all fragments<br />
    20. 20. Database of Replacement Moieties<br />Series of commercial compounds<br />fragmented and recombined<br />Resultant moieties placed into separate databases based on frequency<br />V. Common <br />Common <br />Less Common <br />Rare <br />Very Rare<br />Frequency roughly correlates with synthesizability<br />Add your own database containing proprietary moieties<br />
    21. 21. Example - COX-2<br />Search for Bioisosteres for cyclic lactone of Rofecoxib<br />Search Common Dbs<br />Actives:<br />9 of the first 10 clusters<br />21 of the first 30 clusters <br />87,225 frags<br />
    22. 22. COX-2 Results<br />
    23. 23. COX-2 Results<br />
    24. 24. Product Space<br />Result 1,484<br />Target<br />Result 5<br />
    25. 25. Cross Scoring<br />Separate target and reference for scoring<br />Bring in interactions from a parallel series<br />Multiple series using different parts of a binding site<br />Optimize a low activity series using a high activity “template”<br />Grow molecules<br />Mimic interactions of alternative series<br />Fragment growing<br />
    26. 26. Select a region to replace and remove these atoms<br />Search database for matching fragments<br />(geometric search only)<br />(search runs on fragment conformations)<br />Form Products<br />(minimise and add Field Points)<br />Score<br />FieldStere’s Approach<br />0.68<br />0.78<br />
    27. 27. Cross scoring example - BACE<br />Multiple known actives for BACE<br />Binding site has flexibility<br />Ligand based methods less sensitive to protein movements<br />Ligands interact with the catalytic Aspartates differently<br />
    28. 28. PDB 2IQG - Hydroxyethylamine based inhibitor<br />Complex chemistry<br />Chiral<br />PDB 3L59 - Small guanidine based inhibitor<br />Excellent interactions with Asp’s<br />BACE Experiment<br />
    29. 29. 2IQG - Detail<br />
    30. 30. 3L59 - Detail<br />
    31. 31. Can we use 3L59 to improve 2IQG ?<br />Use 2IQG as the “Target”<br />Score replacements against 3L59 - the “Reference”<br />Region to be replaced<br />Only accept replacements with Carbon here<br />
    32. 32. Preliminary Results<br />Result 18<br />Result 31<br />Result 55<br />Result 83<br />Result 42<br />Result 110<br />
    33. 33.
    34. 34. Cross Scoring 2 - Fragment Growing<br />FieldStere version 3.0.0 fragment growth example:<br />P38 kinase bound to a fragment fluorescent probe PDB:3K3I specific to the ‘DFG-out’ conformation <br />‘DFG-in’ example with specificity towards the ‘Gly’ flipped hinge PDB:3ROC and/or 3HUB<br />Selectivity potentially to be gained by combining ‘Gly flip’ and ‘DFG-out’ in one molecule<br />Can we use the new version of FieldStere to grow the DFG-out fragment into the DFG-in hinge?*<br />*we realize we don’t want to develop a fluorescent probe….but… as an illustration of utility it is OK. We also have a number of more reasonable edits of this fragment….<br />
    35. 35. Fragment in DFG-out pocket, PDB:3K3I <br />predominant hinge<br />conformation<br />
    36. 36. +Gly hinge flip ligand_1, PDB:3ROC <br />Hinge Gly flip<br />
    37. 37. +Gly hinge flip ligand_2, PDB:3HUB <br />Hinge Gly flip<br />
    38. 38. Fieldstere input<br />Target was PDB: 3K3I<br />Reference was PDB: 3ROC<br />20/80 scoring T to R<br />All databases<br />Accurate settings<br />Size limit on fragment removed<br />Fragments limited to 3 rotatable bonds<br />Fragment must contain a ring<br />
    39. 39. Fieldstere output: 2D mols<br />
    40. 40. Fieldstere output: 3D mols<br />Fragment and reference<br />Rank 4<br />Rank 6<br />Rank 11<br />Rank 13<br />Rank 53<br />
    41. 41. Fieldstere output: 3D mols and Fields<br />Fragment and reference<br />Rank 4<br />Rank 6<br />Rank 11<br />Rank 13<br />Rank 53<br />
    42. 42. Fieldstere output: 3D overlay<br />References and Rank 6<br />
    43. 43. Outcome<br />Fragment growth both possible and a facile process using FieldStere<br />Interesting and sensible candidate molecules generated<br />Many more options available for increasing diversity of the output<br />
    44. 44. mark@cresset-bmd.com<br />Questions welcomed<br />
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