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Fast Computational Method for Fragment Growing and Joining Using Molecular Fields
Dr Martin J Slater
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Cresset 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
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Cresset’s unique technology
> It 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 Representation
What chemists see?= Positive = Negative
= Shape= Hydrophobic
What our CPUs see?
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> Field patterns from Cresset’s proprietary XED force field reproduce experimental results
XEDs make fields work
Interaction of Acetone and Any-OH from small molecule
crystal structures
Experimental Using XEDs
C O
-0.5
-0.5
-0.5
-0.5
-0.5
-1.75
-1.75
+5
+1
H
-0.5
-0.5
+0.9+0.1
Not using XEDs
XED adds p-orbitals to get better representation of atoms
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Biologically Relevant Molecular Comparisons
Bioisosteres
Bioisosteric groups
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View fields
N FNO
Field points give you new insights into your molecule
Experimental
(Data from small molecule xray
structures)
Fields
Structure
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Comparing 2D and 3D metrics
Similar 2D=3D_FS
2D=3DDissimilar 2D=3D_FS
2D = 3D_FS
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Example - Higher 3D Sim
2D sim = 0.1(other methods=0.3)
SO Br
N
HNO
3D field sim = 0.82
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O
O
Example - Higher 3D Sim
141
2D sim = 0.2
3D sim = 0.7
454
O
O
HN
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Spark’s Approach
Rofecoxib
Valdecoxib
Etoricoxib
12nM
> Find bioisosteres by replacing sections of the molecule
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Spark’s Approach
1 Select a region to replace and remove these atoms
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Wrong distance
Spark’s Approach
1 Select a region to replace and remove these atoms2 Search database for matching fragments
(geometric search only)(search runs on fragment conformations)
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Spark’s Approach
Wrong angle
1 Select a region to replace and remove these atoms2 Search database for matching fragments
(geometric search only)(search runs on fragment conformations)
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1 Select a region to replace and remove these atoms2 Search database for matching fragments
• geometric search only(search runs on fragment conformations)
3 Form Products• minimise and add field points
Spark’s Approach
Good match
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1 Select a region to replace and remove these atoms2 Search database for matching fragments
• geometric search only• search runs on fragment conformations
3 Form Products• minimise and add field points
4 Score
Spark’s Approach
0.88
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> Produces more diverse, non-obvious bioisosteres> Avoids fragment scoring
limitations> Allows for electronic influence of
replacing a moiety on the rest of the molecule and vice versa
> Allows for neighbouring group effects
Whole-Molecule Scoring Advantages
OO
S OO
SN
S OO
NN
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Example - COX-2
> Search for Bioisosteres for cyclic lactone of Rofecoxib
O O
SOO
aromatic atoms only
Actives:9 of the first 10 clusters21 of the first 30 clusters
Search Common Dbs
87,225 frags
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Cluster, Result Nos
Cluster id
FieldStere result 2D sim closest lit compd
10,12 0.52 Same, 60nM
13,19 0.509
7nM
32, 104 0.48 None
COX-2 Results
Cluster, Result Nos
Cluster id SPARK result 2D sim closest lit
compd
1,1 0.646
2,2 0.531
6.5uM
5,5 0.500 Same, 10nM
9,11 0.532
70nM
ON
SO
O
ON
SO
OH2N
ON
NNS
SO
O
NNS
SO
O
NNS
F
NS
NN
SO
O
NS
NN
S
SO
O
S
O NH2
SO
OH2N
S
O O
N
SO
O
N
SO
O
F
F
SO
O
F
F
F
N NNN
SO
O
N NNN
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Scaffold replacement ‘Sildanafil’
spark (10 mins)NEAT?
spark results 2-5
Fsim score 0.985 0.985 0.982 0.978
spark results 6, 7, 10, 13
Fsim score 0.973 0.973 0.959 0.957
spark results 14, 18, 26, 30
Fsim score 0.953 0.951 0.943 0.939
HN
NO
O
HN
N
NN
O
HN
N NN
O
HN
NN
N
O
S
NN
N
O
O
NN
N
O
HN
N N
N
O
O NN
HN
N
O
ON
N
O
HN
N
N
O
HN
NN
O
N
NHN
N
O
O
Pfizer J. Chem. Inf. Model. 2012
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Fragment growing example
> FieldStere version 3.0.0 fragment growth example:
1. P38 kinase bound to a fragment fluorescent probe PDB:3K3I specific to the ‘DFG-out’ conformation
2. ‘DFG-in’ example with specificity towards the ‘Gly’ flipped hinge PDB:3ROC and/or 3HUB
> Selectivity potentially to be gained by combining ‘Gly flip’ and ‘DFG-out’ in one molecule
> Can we use the new version of SparkV10 to grow the DFG-out fragment into the DFG-in hinge?
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Fragment in DFG-out pocket, PDB:3K3I
predominant hingeconformation
Graphics from Pymol from Delano Scientific
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+Gly hinge flip ligand_1, PDB:3ROC
Hinge Gly flip
Graphics from Pymol from Delano Scientific
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Fragment compatibility – DFG-out
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Structure Rank Sim Structure Rank Sim
1 0.528 11 0.492
4 0.507 13 0.489
6 0.501 53 0.476
Fieldstere output: 2D mols
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Fieldstere output: 3D mols and fields
Fragment and reference Rank 4 Rank 6
Rank 11 Rank 13 Rank 53
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Outcome
> Fragment 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
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Any relevance? – Pfizer compound for COPD
Deposited in PDB: 2YIS November 2011
Clinical trials for COPD
Virtual compounds in the output list……prepared for ACS San Diego Late Summer 2011
S
OH
N
NN
S
NH
ONH
NN OH
F
N
NN
NHN
Br
N
S
O
SH2N H
N
N
Br
O
NH2
O
N
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Conclusion
> Cresset offer a wide variety of software and collaborative solutions for drug discovery
> Cutting edge technology
> Provide key insights
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[email protected] welcomed