The OneStep Server

1
The OneStep Server
Virtual Library Synthesis for In-Silico Lead
Optimisation
Martin Ott Gijs Schaftenaar
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Contents

• Problem Setting
• The Tools
• Web Interface
• Things to Do

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In Silico Lead Optimisation

• The development of pharmacologically active
  compounds is supported by programs which may
  generate in silico structural variants of lead
  molecules.
• Problem These variants may be very difficult to
  synthesise!

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Lego-like Structure Generation
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The OneStep Server

• Solution Base the method of in silico structural
  variation on synthesis!
• Combine a number of Cheminformatics tools to
  generate reaction products and evaluate these
  (e.g., by docking)

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The Tools

• FlexX - Receptor modeling
• What If - Receptor
  refinement
• LCOLI (LHASA) - (Retro)Synthesis
• Corina - 2D to 3D conversion
• Sybyl - Energy minimisation

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Processing Scheme
Sort by score select
Lead ProDrg
Synthesis LHASA
Docking FlexX
Receptor What If
Filter select
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Docking Step
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Receptor Refinement

• What If as refinement tool
• Correction of bond lengths and angles
• Optimisation of hydrogen bonding network
• Possible flips of HIS, GLN, and ASN
• Fast energy minimisation with GROMOS

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FlexX

• Receptor is treated as rigid
• Dock Ligand
• Break Ligand up into rigid fragments
• Dock fragments into pocket of receptor
• Reassemble ligand from docked fragments

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Lead Processing
User input
ProDrg
Ligand 0
LHASA
Ligand 1
Ligand n

Sybyl
Corina
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LHASA / LCOLI
LHASA for COmbinatorial LIbraries Logic and
Heuristics Applied to Synthetic Analysis
E.J. Corey, A.K. Long Harvard University http//lh
asa.harvard.edu
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Some Terminology
Target
Transform
Precursor

Tree
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Principal Features of LHASA

• Logic and Heuristics Applied to Synthetic
  Analysis
• Synthesis planning aid
• Rigorously retrosynthetic
• User directs analysis strategy selection,
  depth, precursor selection
• Chemical knowledge base transforms and a
  description of their scope
• Application of empirical rules

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Mode of Operation

• User draws a target molecule and selects a
  strategy for retrosynthetic analysis
• LHASA applies appropriate transforms and
  displays the precursors
• User may proceed to deepen the analysis
• LHASA displays the retrosynthetic tree for
  re-examination of transforms and precursors
• User selects a new strategy for the target
  or
• User selects precursor(s) for further analysis

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Mode of Operation
Draw target
Start
Select strategy
Select precursor
Examine tree
No
Other strategy?
Endpoint reached?
Done
Yes
No
Yes
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Sample Transform Application
HELP REFERENCE VIEW TREE STOP CONTINUE
50 25 75 1 2
Initial Rating Increment Final Rating Lineage
Acyloin Condensation Actual Conditions Na and
TMSCl in Toluene
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Sample Transform Source Text
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Chemical Knowledge in LHASA
Knowledge base contents 2239 transforms
(retro-reactions) 493 tactical transform
combinations 20 structure perception
transforms 78 FG perception transforms
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Synthesis, Not Retrosynthesis!

• Transforms are used to generate products
• Pattern matching use of precursor 2-D pattern
• Sizable reaction partners are absent
• Only attachment of small fragments which are
  very much standardized (methyl!)

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Sample Lead Androstenone
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Sample Products from Androstenone
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Product Generation
Tripos MOL2 (products)
Tripos MOL2 (lead)
CvtStr
CvtStr
MDL SDFile (products)
MDL MolFile (lead)
LCOLI
Corina
CvtStr
MDL SDFile (products)
LHASA File (lead)
LHASA File (products)

CvtStr
CvtStr
PostScript (lead)
PostScript (products)
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Web Interface Input


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Web Interface Processing
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Web Interface Products
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Things to Do - FlexX

• OH torsion angles of SER, THR, TYR
• Correctly protonated form of ligands
• Receptor flexibility (Concoord)
• Dimer pockets

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Things to Do - Synthesis

• Retain useful synthetic intermediates
• Small building blocks (other than just Me)
• LCOLI should generate all diastereomers
• New synthetic methodology

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Things to Do - Filters

• ADME/Tox filters
• Lipinskis rules of five
• Local structural variation

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Acknowledgements
Gijs Schaftenaar Web interface Simon
Folkertsma FlexX receptors Carsten
Albrecht Evaluation Gert Vriend
The idea