August 2010, ACS National meeting, Boston Representation of Markush structures from molecules...

August 2010, ACS National meeting, Boston

Representation of Markush structures — from molecules towards patents

Szabolcs Csepregi

Solutions for Cheminformatics


Contents

• ChemAxon

• What are Markush structures?

• How to get them?

• What can be done with them?– Enumeration– Storage, search

• Challenges in chemical representation

• Under development


ChemAxon

• Cheminformatics toolkits and applications

• HQ: Budapest, Hungary

• Founded: 1998

• Main customers: pharma, biotech, publishing

• 3rd party applications and web sites. (e.g. Integrity, Reaxis, PDB ligand search, ELN-s, registration systems, etc)


ChemAxon

Main products:– Structure drawing & visualization (Marvin family)– Chemical DB tools (JChem family)– Property predictions (Calculator plugins)– Drug discovery tools (Reactor, JKlustor, etc.)

Development strategy: customer-driven


What are Markush structures

and how to get them?


Markush structures

Generic notation for describing many molecules (= Markush library) in a compact form.

Main usage:– Combinatorial chemistry– Chemistry-related patents


Markush structures

• Current features handled:– R-groups– Atom lists, bond lists– Position variation bond– Link nodes– Repeating units– Homology groups

(aryl, alkyl, etc.)


ChemAxon Markush project

Goals:– Extend structural search capabilities to combinatorial Markush

structures– Markush enumeration

Complications:– Practical examples may be very complex, methods using

explicit enumeration may be impossible– Extension of current molecular formats (generic features)

Timeline – Pilot study started in 2005 Q4, – First prototype shown at UGM, 2006 June– Released in JChem 5.0, 2008– Markush DARC format support 5.3.0 2010


How to get Markush structures?

• Drawing – Marvin Sketch



• Patent literature – Markush DARC format (*.vmn)

• Compatible with Thomson Reuters MMS patent Markush database(Test set available.)



Combinatorial chemistry – Reagent clipping 1. Replace reacting group with attachment point

(Reactor tool)

2. Turn fragments to R-group definitions (Molconvert tool)

3. Add a scaffold (Molconvert tool)



Combinatorial chemistry – R-group decomposition1. Filter and identify ligands in chemical library

2. Create Markush structure from R-table

(R-group decomposition tool)


What to do with them?


Markush Enumeration

• Markush enumeration plugin– Full enumeration– Selected parts only– Random enumeration– Calculate library size– Scaffold alignment

and coloring– Markush code– Optional example

homology groupenumeration


Markush storage & search

• JChem Base and Instant JChem

• No enumeration involved

• Can handle complex Markush structures (1040 or more)

• Substructure and Full structure search

• Broad translation of homology groups is supported. (Homology in DB, specific in query.)



Substructure hit visualization

Query

Result in original Markush



Substructure hit visualization: „Markush structure reduction”

Query

Result in original Markush

Reduced result


Main use cases

• Patent search hits refining / visualization,

• White space analysis,

• Patent busting,

• Markush structure curation,

• In-house storage of small Markush DB,

• etc...


MMS evaluation Instant JChem project


Challenges in chemical representation(solved)


Representation - What we already had

Generic notation in queries:

• Atom lists, bond lists

• R-group queries (Problem: RGFile R-logic and patent R-logic are different! - Solution: Just ignore R-logic.)

• Link nodes

• Some generic atoms (X) – represented as pseudo atoms.

Single or doubleSingle or double


Challenge 1: Attachment point

• Multiple – ligand order and attachment orderHeavily used in Markush DARC (up to 8 attachments!)

• Represented as atom property

Parent group(root)

R-group definitions

Order of ligands for G15 (R15)

Order of ligands for G15 (R15)

Attachment points for definitions




• Embedded R-groups: Grandparent relations may be needed between attachment points:

G3’s attachment point „1” is mapped to

G4’s attachment point „1”

G3’s attachment point „1” is mapped to

G4’s attachment point „1”



• Temporary representation: attached data– ligand order– attachment point in R-group definition– still an atom property– ligand order sometimes in parent group

(grandparent relation)

Order of ligands for R2






• Real attachment object with bond (under development)

– eliminates need for grandparent relations table:



Attachment point for R3

Attachment point for R3






Challenge 2: Abbreviations

• Superatom S-groups were originally in Marvin (~700 built-in shortcuts)– Expand / Contract – Search code already handled them

in specific structures.

• M. DARC had 21 shortcuts + 31 peptides.

• Attachment point next to abbreviations– Needed to be visible „outside” and handled

correctly „inside”.– New attachment point solves this also:


Challenge 3: Homology groups (generics)

• Pseudoatom representation

• Naming (Still looking for the most descriptive „long” names.)

• Extra conditions: general atom property framework (under development)

Markush DARC name „Long name”

CHK alkyl

CYC carboAlicyclyl

ARY carboAryl

HEA heteroMonoAryl


Challenge 4: Frequency variation

• Link nodes

• Repeating units: modified SRU

• Multipliers: – special SRU, 1 outer bonds. – (Currently visualization only.)

• Moieties: – special SRU, 0 outer bonds – to describe (variable) stoichiometry– (Currently visualization only.)


Challenge 5: Position variation bond

• New special S-group type

• Relocatable multicenter atom represents group for bonds

• Also useful to represent multicenter charge and coordination compounds:


What (else) keep us busy


Under development

• Further improvements in Markush DARC support:– Ring segment groups (XX form a ring)

– New, more robust representation for attachment points

– Homology properties (low alkyl, fused aryl, C1-3, N2-5, etc)

• Ranking of results

• New ways to navigate/zoom Markush structures

• Maximum common substructure search

• Biased enumeration and covering Markush – based on examples in patent.

• Improve search speed to handle larger Markush sets.

• Other Markush formats – Markush InChI standard committee

• Overlap analysis of Markush structures

• Conditions for Markush variables


Summary

• Markush structure storage, search and enumeration at ChemAxon now patent coverage

• Compatible patent data is available from Thomson Reuters

• Well thought out chemical representation

• Continuous development, improvements in the pipeline


Acknowledgements

• Development team: Nóra Máté, Róbert Wágner, Szilárd Dóránt, Tamás Csizmazia, Tim Dudgeon, Erika Bíró, Ali Baharev, Ferenc Csizmadia, et al.

• Tim Miller, Steve Hajkowski, Gez Cross and Linda Clark at Thomson Reuters for useful discussions, help and example Markush DARC files

• Many early adopters and colleagues within the field for suggestions and feedback

August 2010, ACS National meeting, Boston Representation of Markush structures from molecules...

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