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Fast Computational Method for Fragment Growing and Joining Using Molecular FieldsDr Martin J SlaterCresset BMD: Who are we?Cresset was founded in 2002 by innovator Andy Vinter We provide and continually develop a suite of unique cutting edge molecular modelling software for drug discovery.We have clients from big pharma, agrochem, biotech and academia

Cressets unique technologyIt uses a condensed 3D representation of the electrostatic, hydrophobic and shape properties of molecules together with the full fields.

3D Molecular Electrostatic Potential (MEP)What proteins see?Field Points2D RepresentationWhat chemists see?= Positive = Negative= Shape= HydrophobicWhat our CPUs see?Field patterns from Cressets proprietary XED force field reproduce experimental resultsXEDs make fields work

Interaction of Acetone and Any-OH from small molecule crystal structuresExperimental

Using XEDs

Not using XEDsXED adds p-orbitals to get better representation of atoms4

Biologically Relevant Molecular Comparisons

BioisosteresBioisosteric groups

5

View fields

Field points give you new insights into your moleculeExperimental(Data from small molecule xray structures)FieldsStructure

Comparing 2D and 3D metricsSimilar 2D=3D_FS2D=3DDissimilar 2D=3D_FS2D = 3D_FS

7Example - Higher 3D Sim2D sim = 0.1(other methods=0.3)

3D field sim = 0.82

Example - Higher 3D Sim

1412D sim = 0.23D sim = 0.7454

Sparks Approach

RofecoxibValdecoxibEtoricoxib12nM

Find bioisosteres by replacing sections of the molecule

Sparks ApproachSelect a region to replace and remove these atoms

Notes:

sparkV10 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. SparkV10 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.11Wrong distance

Sparks ApproachSelect a region to replace and remove these atomsSearch database for matching fragments(geometric search only)(search runs on fragment conformations)

Notes:

SparkV10 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. SparkV10 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.12

Sparks ApproachWrong angleSelect a region to replace and remove these atomsSearch database for matching fragments(geometric search only)(search runs on fragment conformations)

Notes:

SparkV10 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. SparkV10 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.13Select a region to replace and remove these atomsSearch database for matching fragmentsgeometric search only(search runs on fragment conformations)Form Productsminimise and add field points

Sparks Approach

Good match

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.14Select a region to replace and remove these atomsSearch database for matching fragmentsgeometric search onlysearch runs on fragment conformationsForm Productsminimise and add field pointsScoreSparks Approach

0.88

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.15Produces more diverse, non-obvious bioisosteresAvoids fragment scoring limitationsAllows for electronic influence of replacing a moiety on the rest of the molecule and vice versaAllows for neighbouring group effects

Whole-Molecule Scoring Advantages

Notes:

SparkV10s 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.16Example - COX-2Search for Bioisosteres for cyclic lactone of Rofecoxib

Actives:9 of the first 10 clusters21 of the first 30 clusters Search Common Dbs87,225 frags

Cluster, Result NosCluster idFieldStere result2D simclosest lit compd10,120.52Same, 60nM13,190.509 7nM32, 1040.48NoneCOX-2 ResultsCluster, Result NosCluster idSPARK result2D simclosest lit compd1,10.6462,20.5316.5uM5,50.500Same, 10nM9,110.53270nM

Scaffold replacement Sildanafil

spark (10 mins)

NEAT?spark results 2-5Fsim score0.9850.9850.9820.978spark results 6, 7, 10, 13Fsim score0.9730.9730.9590.957spark results 14, 18, 26, 30Fsim score0.9530.9510.9430.939

Pfizer J. Chem. Inf. Model. 2012

Fragment growing exampleFieldStere version 3.0.0 fragment growth example:P38 kinase bound to a fragment fluorescent probe PDB:3K3I specific to the DFG-out conformation DFG-in example with specificity towards the Gly flipped hinge PDB:3ROC and/or 3HUBSelectivity potentially to be gained by combining Gly flip and DFG-out in one moleculeCan we use the new version of SparkV10 to grow the DFG-out fragment into the DFG-in hinge?

Fragment in DFG-out pocket, PDB:3K3I

predominant hingeconformationGraphics from Pymol from Delano Scientific+Gly hinge flip ligand_1, PDB:3ROC

Hinge Gly flipGraphics from Pymol from Delano ScientificFragment compatibility DFG-out

StructureRankSimStructureRankSim10.528110.49240.507130.48960.501530.476Fieldstere output: 2D mols

Fieldstere output: 3D mols and fields

Fragment and referenceRank 4Rank 6Rank 11Rank 13Rank 53OutcomeFragment growth both possible and a facile using an automated process with SparkV10

Interesting and sensible candidate molecules generated

Predict highly selective p38 actives

Absolute requirement for 3D insight

Any relevance? Pfizer compound for COPDDeposited in PDB: 2YIS November 2011Clinical trials for COPDVirtual compounds in the output listprepared for ACS San Diego Late Summer 2011

ConclusionCresset offer a wide variety of software and collaborative solutions for drug discovery

Cutting edge technology

Provide key insights

martin@cresset-group.comQuestions welcomed

COX-2 Results

Product Space

TargetResult 5Result 1,484+Gly hinge flip ligand_2, PDB:3HUB

Hinge Gly flip