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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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Evaluating Bioisosteric Replacements Taking the Whole Molecule into Account
Mark Mackey
Current Versions
Product GUI CLI Next release
FieldScreen (Virtual Screening) 2.6.0 2.6.0 Q1 2012
FieldStere (Bioisosteric groups) 2.0.0 2.1.0 October 2011
FieldAlign (Ligand alignment and design) 3.0.1 3.0.1 Q4 2011 (as Molecular Architect)
FieldTemplater (3D pharmacophore determination)
3.0.0 - Q2/3 2012
FieldView (Viewer) 2.0.2 - Q1 2012
XedTools (Conformations, Ligand Minimizer)
- 2.6.0 Q1 2012
NN
Br
F FF
SH2NO
O
Field Points
Condensed representation of electrostatic, hydrophobic and shape properties (“protein’s view”)
> Molecular Field Extrema (“Field Points”)
3D Molecular Electrostatic
Potential (MEP)
Field Points= Positive = Negative= Shape= Hydrophobic
2D
H-bond donor
H-bond acceptor
Hydrophobes
Aromatic p cloud
‘H acceptor’
Aromatic in-plane
‘H donor’
-ve ionic
+ve ionic
“Stickiest” surfaces (high vdW)
N
NH
O
O
OH H
H
Explanatory Power of Fields
Field points give you new insights into your molecule
= Positive = Negative= Shape= Hydrophobic
Field point size show importance
FieldStere
> Finding bioisosteres by replacing sections of the molecule
Rofecoxib
Valdecoxib
Etoricoxib
12nM
FieldStere’s Approach
1 Select a region to replace and remove these atoms
FieldStere’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)
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)
FieldStere’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)
3 Form Products(minimise and add Field Points)
4 Score
FieldStere’s Approach
0.88
> 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
Database of Replacement Moieties
> Series of commercial compounds> fragmented and recombined
> Resultant moieties placed into separate databases based on frequency> V. Common
> Common
> Less Common
> Rare
> Very Rare
> Frequency roughly correlates with synthesizability
> Add your own database containing proprietary moieties
Example - COX-2
> Search for Bioisosteres for cyclic lactone of Rofecoxib
O O
SO
O
aromatic atoms only
Actives:9 of the first 10 clusters21 of the first 30 clusters
Search Common Dbs
87,225 frags
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
FieldStere 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
N
N
SO
O
NS
N
N
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 NN
N
SO
O
N NN
N
COX-2 Results
Product Space
Target Result 5 Result 1,484
Cross Scoring
> Separate target and reference for scoring
> Bring in interactions from a parallel series> Multiple series using different parts of a binding site
> Optimize a low activity series using a high activity “template”
> Grow molecules> Mimic interactions of alternative series
> Fragment growing
S
N
S
O
O
N
N
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
FieldStere’s Approach
0.680.78
Cross scoring example - BACE
> Multiple known actives for BACE
> Binding site has flexibility> Ligand based methods less sensitive to protein
movements
> Ligands interact with the catalytic Aspartates differently
> PDB 2IQG - Hydroxyethylamine based inhibitor> Complex chemistry> Chiral
> PDB 3L59 - Small guanidine based inhibitor> Excellent interactions with
Asp’s
BACE Experiment
NH
O
N
O
NH2+
I
F
F
OH
N
Cl
NH
O NH2+
2IQG - Detail
3L59 - Detail
Can we use 3L59 to improve 2IQG ?
> Use 2IQG as the “Target”
> Score replacements against 3L59 - the “Reference”
NH
O
N
O
NH2+
I
F
F
OH
Region to be replaced
Only accept replacements with Carbon here
Preliminary Results
NH
O
N
O
F
F
SH2N
+HN
NH
O
N
O
F
F
NH
N NN
NH
O
N
O
F
F
O
NH+
NH
O
N
O
F
F
O
H2+
N
NH
O
N
O
F
F
N
NH3+
NH
O
N
O
F
F
NHN
H2+
N
HNH
O
N
O
NH2+
I
F
F
OH
Result 18 Result 31
Result 55 Result 83Result 42
Result 110
Cross Scoring 2 - Fragment Growing
> 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 FieldStere to grow the DFG-out fragment into the DFG-in hinge?*
*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….
Fragment in DFG-out pocket, PDB:3K3I
predominant hingeconformation
+Gly hinge flip ligand_1, PDB:3ROC
Hinge Gly flip
+Gly hinge flip ligand_2, PDB:3HUB
Hinge Gly flip
Fieldstere input
> Target was PDB: 3K3I
> Reference was PDB: 3ROC
> 20/80 scoring T to R
> All databases
> Accurate settings
> Size limit on fragment removed
> Fragments limited to 3 rotatable bonds
> Fragment must contain a ring
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
Fieldstere output: 3D mols
Fragment and reference Rank 4 Rank 6
Rank 11 Rank 13 Rank 53
Fieldstere output: 3D mols and Fields
Fragment and reference Rank 4 Rank 6
Rank 11 Rank 13 Rank 53
Fieldstere output: 3D overlay
> References and Rank 6
Outcome
> Fragment growth both possible and a facile process using FieldStere
> Interesting and sensible candidate molecules generated
> Many more options available for increasing diversity of the output
