experiences with reactor in pipeline pilot - chemaxon · 08.12.2009 · experiences with reactor in...

Experiences with Reactor in Pipeline Pilot

Isabella HaightChemAxon UGMSeptember 15, 2009

Experiences with ReactorSeptember 15, 2009

2Company Confidential© 2009 Abbott

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



Reactor in Pipeline Pilot

•

Supports "smart" reactions

–

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

New Upgrades



Reactor Library Reactions:

Bischler-Mohlau Indole

Synthesis

•

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

Acetophenone Aniline 2-Arylindole



Reactor Library Reactions:

Suzuki Coupling

Organo-boron Halide or Pseudo-halide C-C Coupled

•

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



CombiChem

Example Using Reactor Library

S

O

Br

+

Cl

NH N

Cl

S+ HBr

N

B

OH

OH

N

S

N

1. Bischler-Mohlau Indole Synthesis

2. Suzuki Coupling

CC13105 TL00240

CC04212

Suzuki_coupling(CC04212, Bischler-Mohlau Indole(CC13105, TL00240):1/1):1/1

Bischler-Mohlau Indole(CC13105, TL00240):1/1

Synthesis Code Generation:

R1(A1,B1):1/1



Reaction Rules in Reactor

Reaction Rules ON OFF

1. Bischler-Mohlau(10 Ketones

x 20 Amines)

51(200)

310(200)

2. Suzuki (Indoles

x 10 Boron)

30(510)

3380(3100)

•

Reactions Rules: ON

–

May yield fewer results than theoretical since REACTOR eliminates starting materials that are synthetically unfeasible

•

Reaction Rules: OFF

–

Could use for debugging purposes–

May yield more results than theoretical since the reactions are interpreted generically



Reaction Rules OFF –

Caution!

Reactivity: O is organo-sulfonate

( “pseudo-halogen”)

NHO

HN

N

O 22

N

12

NHO

HN

N

N

12

N

BOHHO 3

1 +

+

Bischler-Mohlau Indole(F1011-0534, F0074-0075):2/1)CC04212

Suzuki Coupling

Suzuki_coupling(CC04212, Bischler-Mohlau Indole(F1011-0534, F0074-0075):2/1):1/1Suzuki_coupling(CC04212, Bischler-Mohlau Indole(F1011-0534, F0074-0075):2/1):2/1

4

(Generic interpretation of reaction!)

Incorrect Product

Synthetically Unfeasible

Product

Suzuki Coupling



Protocol Summary

1.

Search for applicable starting materials.

2.

Run ChemAxon Reactor to do combinatorial chemistry.

3.

Filter and Cluster output to obtain sampling of reaction.

1 2 3



Pre-filter Starting Materials?

• Searched Maybridge

for reagents

–

Building Block catalogue contains 6458 compounds

Ar

O

H

NH

X

H

NAr

Bischler-Mohlau Indole Synthesis

+

X = N,O,Cl,Br,I

Maybridge

BB Ketones Amines Combinations Products Time (hrs)Pre-Filter 98 470 47,060 23,674 0:10

Entire catalogue 6458 6458 41,705,764 23,674 7:07

More efficient to pre-filter starting materials



Starting Materials

1.

Combined two vendor Building Blocks catalogues

–

Life Chemical (5701 compounds)–

Maybridge

(6458 compounds)–

TOTAL available Building Blocks: 12,159

2.

Used generic queries to find starting materials

–

Reactor will apply reactivity rules to select best reagents

3.

Cluster query hits to keep numbers manageable

Ketone Aniline Boron

Query B

Hits 124 941 250Clusters 57 383 98

Ar

OX

H

X = N,O,Cl,Br,I

HN

H



ChemAxon Reactor



Filter-Cluster Subprotocol

•

Lipinski (“Rule-of-Five”) filter to obtain drug-like products

•

Cluster output

–

Reaction sampling–

Keep numbers manageable



Pipeline Pilot Protocol for CombiChem

Example



Virtual Database of CombiChem

Products with Synthesis Codes

2-step reactions

1-step reactions



Synthesis Code GeneratorAdvantages

•

Tracks starting material identifiers

•

Can capture reaction name/type

•

Generates a unique product identifier for each enumerated product

Disadvantages•

Unable to associate source (vendor) with identifier

•

Identifiers are arbitrary

•

Compound identifiers are not descriptive of structure

•

Compound identifiers can change over time!

Suzuki_coupling(CC04212, Bischler-Mohlau Indole(SEW02738, BTB07447):1/1):1/1Suzuki_coupling(CC04212, Bischler-Mohlau Indole(SEW02738, BTB07447):1/1):2/1

HN

NH2

N

Cl

HN

NH2

Cl

N



Virtual Database with Reactions

BrCC(=O)c1nccs1.CC(C)c1ccccc1N>>CC(C)c1cccc2cc([nH]c12)c3nccs3

Reaction SMI can be readily parsed to get reactants and products



ChemAxon Reactor Allows for Reaction Output Option

These options are turned off in Reaction

mode



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



Reaction Protocol Summary -

Modified

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)

1 32

45



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



Reactor within Pipeline Pilot Allows for Streamlined Manipulation of Reaction Data

23

Virtual Compound Database with ReactionsC

an o

nly

stor

e 1-

step

reac

tions



Parse RXNSMI to get Reactants



Look Up Reactants in Any Database

(Maintain an in-house database of compiled vendor compounds)



Parse RXNSMI from 2-step Reaction



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.



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



Questions?

experiences with reactor in pipeline pilot - chemaxon · 08.12.2009 · experiences with reactor in...

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