Small molecules and reaction mechanism -

Rewiring the enzyme space

Syed Asad Rahman

E-mail: asad@ebi.ac.uk

CDKWS- 2009

04/21/2009 EBI is an Outstation of the European Molecular Biology Laboratory. 
Overview
• Understanding Metabolic Networks
• Shortest path based conversion of substrate to product
• Challenges and some meaningful solution
• Pathway Hunter Tool (PHT)

• Small Molecule similarity and its impact

• Fingerprint vs Maximum Common Subgraph
• SMSD (Small Molecule Subgraph Detector)

• EC classification
• Do the represent the bonds of Life or are they like computer IP address?
• A step towards reaction homologues and its impact on EC classification
• Transition state analogues
• ERI (Enzyme Reaction Information)-Toolkit
Enzyme and reaction

3 1 5
1

E1 E2 2

5
2

3
FINDING SHORTEST PATH
BIOCHEMICAL NETWORKS

Automated metabolic network reconstruction

 This figure exemplifies the problem of finding a valid
shortest path in the biochemical network

Rahman, S. A. et al. Bioinformatics 2005 21:1189-1193;

doi:10.1093/bioinformatics/bti116

Copyright restrictions may apply.

 Mapping Reactant and Product

Understanding patterns in reactions

Rahman, S. A. et al. Bioinformatics 2005 21:1189-1193;

doi:10.1093/bioinformatics/bti116

Pathway Hunter Tool (PHT) – A Platform for Metabolic Network Analysis

and Potential Drug Targeting (PhD Thesis 2006)

http://kups.ub.uni-koeln.de/volltexte/2008/2450/

Copyright restrictions may apply.

Connectivity Analysis: Metabolic
Centric View

Google: Pathway Hunter Tool (PHT)

Tracing Atom(s) in the Pathway

• ARM (http://www.metabolome.jp)
• PHT (http://pht.tu-bs.de/PHT/)
SIMILARITY SEARCH

Small Molecule Similarity

Reaction Similarity
Matching Chemical Moieties
• Index of pattern matching
• Similarity (i.e. Tanimoto co-efficient)
• Distance (i.e. Euclidean )
• Finding similar molecules (i.e. substructure)
• MCS (Maximum common subgraph)
• + Very good for substructure search
• + Pinpoints the common patterns
• - Computation exhaustive
• Fingerprints (Descriptors of chemical moieties)
• + Fast and descriptor depended
• + Very good for reporting overall similarity and size of the
molecule
• - Can’t map the matched patterns on the query molecule
Maximum Common Subgraph (MCS)
Few words about CDK MCS
• Its very fast when two molecules are very similar!
Except
• MICS (Maximum Common Induced Edges), hence treats
cyclopropane and Isobutane as similar molecules

• Rings structures differ at non-ring sites

• Ranking the MCS solutions

 Introducing a new Maximum Common Subgraph (MCS) calculation
software

SMALL MOLECULE SUBGRAPH

DETECTOR (SMSD)

http://www.ebi.ac.uk/thornton-srv/software/SMSD/

OR
Google: SMSD + EBI

http://www.ebi.ac.uk/thornton-srv/software/SMSD/cdkws2009.zip
MCS vs. SMSD
Fingerprint vs. SMSD (~50,000 pairwise comparison)

Tanimoto score = ~ 0.50 as 99 percentile of the data is covered

~ 0.77 as 99.9 percentile of the data is covered
Acknowledgement

• Franz Fenninger
• Dr. Lorenzo Baldacci

• Dr. Gemma L. Holliday

• Dr. Kazuto Yamazaki
• Dr. Matthew Bashton
Prof. Janet M. Thornton Prof. R. Schrader

• Special thanks to CDK development team

• Chemistry Development Kit (CDK)
• Chemaxon
• Open Babel

Prof. D. Schomburg
THANK YOU!

Syed Asad Rahman

E-mail: asad@ebi.ac.uk

Skype: s9asad