Experiences with Reactor in
Pipeline Pilot
Isabella Haight
ChemAxon UGM
September 15, 2009
Synthetically Feasible Virtual Database
• Diverse, virtual library to be used in virtual screening, lead
hopping and lead optimization for drug discovery
– Sampling of chemically accessible space
• Synthetically accessible products
– Well defined reaction scheme
– Readily available starting materials
• Tools
– ChemAxon Reactor
• Enumerate synthetically feasible virtual products
– Pipeline Pilot
• Process the enumerated reactions
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
2
Reactor in Pipeline Pilot
• Supports "smart" reactions
New Upgrades
– generic reaction equations
combined with reaction rules
generating chemically feasible
products
• Reaction library of 145 reactions
• Synthesis code generation
– Unique identifier for product
• Reaction Rules
– Reactivity and Exclude
– Selectivity
– Tolerance
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
3
Reactor Library Reactions: Bischler-Mohlau
Indole Synthesis
Acetophenone
Aniline
2-Arylindole
• Reactivity (select appropriate reagents)
– First reactant is aryl-methyl-ketone with alpha halogen, amino or activated hydroxy
derivative (tosyl, mesyl…)
– Second reactant is aniline not acylated
• Selectivity (finds most reactive sites)
– Aromatic electrophilic substitution goes faster on the most negative carbon
• Exclude (compounds that may yield side reactions)
– Exclude compounds which may react with anilines
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
4
Reactor Library Reactions: Suzuki Coupling
Organo-boron
C-C Coupled
Halide or Pseudo-halide
• Reactivity (select appropriate reagents)
– First reactant is boronic acid, ester or anhydride, borane or trifluoroborate salt
– Second reactant may be halogen or organo-sulfonate or methyl sulfide (behave as
pseudo-halogen)
• Selectivity (finds most reactive sites)
– The most negative carbon atom reacts in oxidative addition from the second
molecule
• Exclude (compounds that may yield side reactions)
– Second reactant may not contain such functional groups which compete with the
boron containing group in the transmetallation step of the catalytic cycle
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
5
CombiChem Example Using Reactor Library
S
+
N
H
O
S
TL00240
+ HBr
N
Cl
Br
CC13105
1. Bischler-Mohlau
Indole Synthesis
Cl
Bischler-Mohlau Indole(CC13105, TL00240):1/1
2. Suzuki
Coupling
Synthesis Code
Generation:
N
B
OH
OH
R1(A1,B1):1/1
CC04212
S
N
N
Suzuki_coupling(CC04212, Bischler-Mohlau Indole(CC13105, TL00240):1/1):1/1
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
6
Reaction Rules in Reactor
• Reactions Rules: ON
Reaction Rules
ON OFF
1. Bischler-Mohlau
51
(10 Ketones x 20 Amines)
(200) (200)
– May yield fewer results than
theoretical since REACTOR
eliminates starting materials that
are synthetically unfeasible
310
• Reaction Rules: OFF
– Could use for debugging purposes
2. Suzuki
30
(Indoles x 10 Boron)
(510) (3100)
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
– May yield more results than
theoretical since the reactions are
interpreted generically
3380
7
Reaction Rules OFF – Caution!
Suzuki Coupling
Reactivity: O is organo-sulfonate
( “pseudo-halogen”)
HO 3 OH
B
O
+
1
NH
N
H
N
CC04212
(Generic interpretation of reaction!)
2
2 O
4
N
Suzuki Coupling
Bischler-Mohlau Indole(F1011-0534, F0074-0075):2/1)
Synthetically
Unfeasible
Product
O
NH
2
N
H
N
2
+
1
N
1
N
Suzuki_coupling(CC04212, Bischler-Mohlau Indole(F1011-0534, F0074-0075):2/1):1/1
Suzuki_coupling(CC04212, Bischler-Mohlau Indole(F1011-0534, F0074-0075):2/1):2/1
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
8
Incorrect
Product
Protocol Summary
1
3
2
1. Search for applicable starting materials.
2. Run ChemAxon Reactor to do combinatorial chemistry.
3. Filter and Cluster output to obtain sampling of reaction.
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
9
Pre-filter Starting Materials?
•
Searched Maybridge for reagents
–
Building Block catalogue contains 6458 compounds
H
H
Ar
X
N
H
+
Bischler-Mohlau
Indole Synthesis
N
Ar
O
X = N,O,Cl,Br,I
Maybridge BB
Pre-Filter
Entire catalogue
Ketones
Amines
Combinations
Products
Time (hrs)
98
470
47,060
23,674
0:10
6458
6458
41,705,764
23,674
7:07
More efficient to pre-filter starting materials
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
10
Starting Materials
1. Combined two vendor Building
Blocks catalogues
–
Life Chemical (5701 compounds)
–
Maybridge (6458 compounds)
–
Reactor will apply reactivity rules
to select best reagents
Query
Company Confidential
© 2009 Abbott
Ar
N
H
X
O
B
X = N,O,Cl,Br,I
Hits
Clusters
3. Cluster query hits to keep
numbers manageable
Experiences with Reactor
September 15, 2009
H
H
TOTAL available Building Blocks:
12,159
2. Used generic queries to find
starting materials
–
Ketone Aniline Boron
11
124
57
941
383
250
98
ChemAxon Reactor
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
12
Filter-Cluster Subprotocol
• Lipinski (“Rule-of-Five”) filter to obtain drug-like products
• Cluster output
– Reaction sampling
– Keep numbers manageable
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
13
Pipeline Pilot Protocol for CombiChem Example
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
14
Virtual Database of CombiChem Products with
Synthesis Codes
2-step reactions
1-step reactions
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
15
Synthesis Code Generator
Advantages
Disadvantages
• Tracks starting material
identifiers
• Unable to associate source (vendor)
with identifier
• Can capture reaction
name/type
• Identifiers are arbitrary
• Generates a unique product
identifier for each
enumerated product
• Compound identifiers are not
descriptive of structure
• Compound identifiers can change
over time!
NH2
NH2
H
N
H
N
Cl
N
Cl
N
Suzuki_coupling(CC04212, Bischler-Mohlau Indole(SEW02738, BTB07447):1/1):1/1
Suzuki_coupling(CC04212, Bischler-Mohlau Indole(SEW02738, BTB07447):1/1):2/1
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
16
Virtual Database with Reactions
Reaction SMI can be readily parsed to get reactants and products
BrCC(=O)c1nccs1.CC(C)c1ccccc1N>>CC(C)c1cccc2cc([nH]c12)c3nccs3
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
17
ChemAxon Reactor Allows for Reaction Output
Option
These options
are turned off
in Reaction
mode
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
18
Working with Reaction Output in Reactor
• Must convert reaction output into single product molecule
– Reaction output is not a single molecule
– Cannot go through Filter-Cluster protocol
– Cannot be used directly as input for next Reactor step
• Reaction output needs to be converted to a RXNSMI for storage
in virtual database
• Pipeline Pilot allows for streamlined manipulations and
conversions of Reactor reaction output
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
19
Reaction Protocol Summary - Modified
1
3
2
4
5
1. Search for applicable starting materials
2. Run ChemAxon Reactor to do combinatorial chemistry
3. Convert reaction output into a single product molecule and into
RXNSMI (new)
4. Filter and Cluster output to obtain sampling of reaction
5. Add reaction name (optional) (new)
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
20
RDF_2_SMI Sub-protocol
• Parses out reaction into reactants and product
• Creates single molecule from product for filtering, clustering and input
into next Reactor step
• Assembles RXNSMI from reactants and product
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
21
Reactor within Pipeline Pilot Allows for Streamlined
Manipulation of Reaction Data
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
22
Can only store 1-step reactions
Virtual Compound Database with Reactions
23
Parse RXNSMI to get Reactants
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
24
Look Up Reactants in Any Database
(Maintain an in-house database of compiled vendor compounds)
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
25
Parse RXNSMI from 2-step Reaction
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
26
2-Step Reaction Reactants Search
(Maintain an in-house database of compiled vendor compounds)
1. Not found in compiled vendors database.
2. Try look-up in virtual database to see if it is
product of another reaction and repeat
reactant search.
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
27
Pipelining Reactor
• ChemAxon Reactor is a useful tool for creating synthetically
feasible virtual databases
– The Reactor Library contains 145 reactions with predefined reaction
rules
– The synthesis code option allows for the creation of a unique
identifier for each combinatorial product
– The reaction output option allows the user to capture all the
reaction information in one format
• The Reactor component in Pipeline Pilot allows for streamlined
manipulation of reaction data and products
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
28
Questions?
Experiences with Reactor
September 15, 2009
Company Confidential
© 2009 Abbott
29