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
2

Markush structures
Generic 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.
3

Markush structures
Combinatorial Markush Patent Markush
• Smaller libraries • The goal is as wide
• Usually simpler coverage as possible
constructs: • Uses more
– R-groups sophisticated methods
– Link nodes – Homology variation
– Atom lists (Alkyl, Aryl, etc.)
– Position variation
• Suitable to describe
– Etc.
simpler patents
• Extra conditions to
avoid overlap with
existing patents
4

Drawing with Marvin
• Easy R-group drawing & zoom functions
• Atom list, link node, bond list
• Position variation New in 5.1
5

Enumeration
• Full enumeration
• Selected parts only
• Random enumeration
• Calculate library size
exact size of huge
Markush libraries
– arbitrary precision or
– magnitude
6

Enumeration
• Coloring: scaffold and each R-group parts get different colors
New in 5.1
• Alignment: as original scaffold
7

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
8

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
9

Integration in Instant JChem 2.3
New in 2.3
• Markush tables available: create, import, insert, search
• Show / hide R-groups for Markush table views
• Markush enumeration / hit reduction dialog
10

What is coming in 5.1
New 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
11

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
12

Thank you for your attention!
For more information please visit
www.chemaxon.com
13