Combinatorial Markush

structures at ChemAxon:

from drawing to analysis

Szabolcs Csepregi

Solutions for Cheminformatics

Outline

• Combinatorial and patent Markush structures

• Drawing Combinatorial Markush structures with

Marvin

• Markush Enumeration

• Markush registration & searching in a database

• What is coming in Marvin / JChem 5.1

• Future plans – towards patents

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Markush structuresGeneric notation for describing many molecules

(= Markush library) in a compact form.

Main usage:

– Combinatorial chemistry: similar steps of synthesis

– Chemistry-related patents: to claim part of the chemical

space for a particular purpose.

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Markush structures

Combinatorial Markush

• Smaller libraries

• Usually simpler

constructs:

– R-groups

– Link nodes

– Atom lists

• Suitable to describe

simpler patents

Patent Markush

• The goal is as wide

coverage as possible

• Uses more

sophisticated methods

– Homology variation

(Alkyl, Aryl, etc.)

– Position variation

– Etc.

• Extra conditions to

avoid overlap with

existing patents4

Drawing with Marvin• Easy R-group drawing & zoom functions

• Atom list, link node, bond list

• Position variation

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New in 5.1

Enumeration

• Full enumeration

• Selected parts only

• Random enumeration

• Calculate library sizeexact size of huge

Markush libraries

– arbitrary precision or

– magnitude

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Enumeration• Coloring: scaffold and each R-group parts get different colors

• Alignment: as original scaffold

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New in 5.1

Markush database tables

• Available in JChem Base and Instant JChem

• Search in the Markush library space of

combinatorial Markush structures

– No enumeration involved – can handle very complex

Markush structures (tested up to 1040, but no explicit limits

were built in.)

– Search types:

• Substructure

• Exact structure (contained in the Markush library)

• Exact fragment

• Perfect (same Markush structure)

– Stereochemistry, query atoms, bonds, query properties:

• Aromatic/aliphatic atom, ring atom and bond, chain bond,

number of bonds handled

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Markush database tables

Markush structure reduction to display substructure hits:

All matchings of the query to the Markush structure are reduced

into less generic structures. (Generic parts overlapping the hit

are expanded.)

Example

Markush structure Reduced Markush structures

with hit coloring

+ Query

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Integration in Instant JChem 2.3• Markush tables available: create, import, insert, search

• Show / hide R-groups for Markush table views

• Markush enumeration / hit reduction dialog

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New in 2.3

What is coming in 5.1

• Drawing

– Easier sketching of position

variation (from 5.0.2)

• Markush features

– Position variation

• Enumeration:

– R-group coloring

– Scaffold alignment

• Markush search:

– Abbreviations (superatom s-groups) can be included in

Markush structures (from 5.0.2)

– Position variation in both query and database

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New in 5.1

Longer term plans

Further developments towards patents

• Homology variation (Alkyl, Aryl, Protecting group, etc.)

– properties (# of atoms, branching points, # of heteroatoms, etc.)

• Multiple graphical attachment points for R-groups

• Larger repeating groups

• Bridged definition of multiple R-atoms R1, R2= H, CH3, NO2 or together form a ring

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Thank you for your attention!

For more information please visit

www.chemaxon.com

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