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A vast virtual chemical space

powered by ChemAxon’ s Markush Search Platform

and its utility in molecular design

Zhengwei Peng

09/26/2014, 2014 ChemAxon UGM, Boston

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Outline

• What are virtual chemical spaces?

• How to search them?

• How to construct them?

• A pilot VL powered by the extended Markush Search

Engine and accessible by users via a web tool

• A wish list

• Summary

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Chemical spaces: Patent Markush and

CombiChem libraries

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Peng, DDT, 2013

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Previous work on vast virtual chemical spaces and related similarity search methods

Z. Peng, (2013) Very large virtual compound spaces: construction, storage, and utility in drug

discovery. Drug Discovery Today: Technologies, http://dx.doi.org/10.1016/j.ddtec.2013.01.004.

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ChemAxon-Merck collaboration (2014) to extend the patent

Markush search engine to handle CombiChem virtual libraries

Hu et al, “LEAP into the Pfizer Global

Virtual Library (PGVL) Space: Creation

of Readily Synthesizable Design Ideas

Automatically”, J.Z. Zhou (ed.),

Chemical Library Design, Methods in

Molecular Biology 685 (2011)

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Extended

ChemAxon

Markush search

Engine

>1012

• EXACT search

• Sub Structure search

• + Similarity search (LEAP2 of Pfizer)

Advantages:

• a single search engine which supports all three search types

commonly used by chemists

• tighter integration to boost performance

• better support and continue improvements

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LEAP2: a similarity search method

Levitra

Step 1: rank R-group

fragments based on

Super Similarity score

between Basis Products

and query molecule.

Step 2: focus on top

ranking fragments and

enumerate a smaller

subset of products.

0 false positive rate, low false negative rate. Tremendous speed-up.

Step 3: perform the standard

similarity comparison between

the query molecule and

enumerated products. Return

search hits.

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Deployed as a service

Extended ChemAxon

Markush Search Engine

REST-ful

API

PLP

connector

Web App PLP protocolsRich GUI App

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Deployed as a service

Web tool Other Mol. design tools

Chem. Informatics Platform & Services

ChemAxon Markush

Search engine

Virtual Libraries

(~1010-18)

Rxns &

building

blocks

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Workflow used to construct & update VL content

Hu et al, Pfizer Global Virtual Library (PGVL): A chemistry design tool powered by

experimentally validated parallel synthesis information, ACS Comb. Sci., 2012, 14, 579-589.

The workflow is implemented using Biovia’s Pipeline Pilot

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Chemistry knowledge/rules captured for re-use

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Hu et al, Pfizer Global Virtual Library (PGVL): A chemistry design tool powered by experimentally validated

parallel synthesis information, ACS Comb. Sci., 2012, 14, 579-589.

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Construction of a sample VL dataset

Hartenfeller et al (Novartis), A collection of

robust organic synthesis reactions for in

silico molecular design, J. Chem. Inf. Model.

2011, 51, 3093-3089

58 Rnxs in combination with ACD

reaction building blocks

a sample VL of 10 10-11

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A pilot web tool to showcase search capabilities

Similarity search time:

• depends on query structure and server load

• ranging 20s to 60s

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Sample search result

Hartenfeller et al. A Collection of Robust

Organic Synthesis Reactions for in Silico

Molecular Design, J. Chem. Inf. Model,

2011, 51, 3093-3098.

Returned info on a search hit:• Library ID

• Rxn ID

• Building block IDs

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Utilities of VLs in molecular design

1) Hit expansion

Given a library hit

retrieve the Rxn used

and associated

suitable reactants,

initiate hit follow-up

library design and

synthesis.

Given a lead structure

retrieve similar

compounds in VL (with

Rxns & corresponding

reactants), initiate

multiple sets of lead

hopping library design

and synthesis.

Virtual Rxns,

reactants, Markush

cores, and R-group

fragments can also

be added into VL for

general design idea

generation and

evaluation.

2) Lead hopping 3) Idea generation

Expected benefits:

• Speed: enable a faster and more cost-effective design/synthesis/test cycle

• Scale: leverage the captured Rxn knowledge by all molecular designers

• Compete: competitive edge (size of VL, diversity in captured Rxns, proprietary

reaction building blocks) at project teams’ finger tips

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Potential areas of applications

• Allow drug discovery project teams to perform in-depth analysis to

facilitate prioritization of proposed scaffolds and/or proposed reactions

• DNA-encoded libraries: enable structure searches and library (as well as

library idea) evaluation and comparisons

• Automatically notify project chemists of possibilities & alternatives…

• ….

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A wish list

• Performance enhancement

• faster library loading

• faster SSS and Exact searching

• High availability and scalability

• many users, many VLs, & many CPUs 10 sec per search

• …an embarrassingly parallel-able search problem…

Opportunity as a community effort with mutual benefits

• many pharma companies are using virtual libraries…

• adoption of the DNA-encoded library production for hit

generation is growing

• with pooled resources, more could be accomplished

An extension framework for customer-built similarity search

methods

• …shape-based, pharmacophore-based, etc.

• ..let (enable via the Platform) the hundred flowers bloom…

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Summary

• The extended Markush Search Engine can now support Exact, SSS,

and Similarity searches into vast virtual spaces spanned by

combinatorial chemical reactions

• Good performance has been seen based on searches against a pilot

VL containing ~1010-12 compounds

• There are still rooms for further innovation and enhancements

• leverage the platform

• A great opportunity for community engagement

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Acknowledgements

• ChemAxon collaborators• Tim Dudgeon, Andras Volford, Peter Borbas, and Doug Drake

• Merck colleagues

• The VL Search team: • Chris Culberson, Brad Feuston, Sookhee Ha, Scott Harrison, Gopal

Parthasarathy, and Bob Sheridan.

• MRL chemistry groups: • Milana Maletic, Zhi-Cai Shi, Graham Smith, and Nunzio Sciammetta.

• MRL-IT: • Chris Brofft and Gang Huang

• Management support: • Chris Waller and Frank Brown