ICIC 2014 Knowledge-Based De Novo Molecular Design Using ICSYNTH FRP
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Transcript of ICIC 2014 Knowledge-Based De Novo Molecular Design Using ICSYNTH FRP
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Knowledge-based
InfoChem GmbH Chemnotia AB
Fernando F. Huerta
powered by
Compound Design
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QSAR models
Ligand Based
Pharmacophore models
Structure Based
HTS
Compound (Drug) Design
Fragment Based
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How Drugs Look?
N
O
OH
ONH2F
FN
HNN
O
OH
ONH2F
FN
HNN
O
OH
ONH2F
FN
HNN
O
OH
OF
FN
HN
Norfloxacin (Noroxin™)
Ciprofloxacin (Cipro™)
Sparfloxacin (Zagam™)
Grepafloxacin (Raxar™)
Drug Discovery Today 2011, 16, 722 Drug Discovery Today 2011, 16, 779
N
HN
SO
NO
O
N
HN
SO
N
O
O
N
HN
SO
N
O O
OF
F
Nexium® Rabeprazole® PANTOPRAZOLE®
O
NN
N
Cl S
NN
N O
HO
Seroquel® Loxapine®
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Protein
Binding
Site
Why Do Drugs Look Similar?
Activity, Selectivity, ADMET,..
Similar structural motif share similar properties(?)
Drug Design Paradigm
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What would you do?
Compound (Drug) Design
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Knowledge-based Compound Design
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Transforms from Reaction Databases
Reaction database e.g. SPRESI
proprietary databases commercial databases
Transform library
1. Pre-processing
Automatic transform extraction
(ICMAP/CLASSIFY)
N
Remove bond 1-3Make new single bond between atoms 3 and 5Remove bond 1-2
Make new single bond between atoms 3 and 4
12
3
O4
5
6
7 8
910
R111
R212
13
14
Template (2 levels):
Transform:
Make new single bond between atoms 2 and 6.
Decrease bond order of double bond 2=4 by 1.
Add group to atom 3: -OH
Remove bond between atoms 3 and 6.
2. Retrosynthesis
Lookup stored
example reactions
Target molecule
O
O
HH
Precursor(s) 1
... Precursor(s) 2
Precursor(s) n ...
Transform x
Transform y
Transform z
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Transforms from Reaction Databases
Reaction database e.g. SPRESI
proprietary databases commercial databases
Transform library
2. Forward Reaction
Lookup stored
example reactions
Starting Material or Reactant
Transform x
Transform y
Transform z
Product(s) 1
... Product(s) 2
Product(s) n ...
N
Cl N
O
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Retrosynthetic Analysis
• Target orientated • Complexity reduction • Availability of starting
materials • Multistep process
Reaction Prediction
• Unknown product molecules
• Molecular size • Reagents • Single reaction step
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Forward Reaction Prediction (cont.)
• Number of transforms
O
S
OHO O
N
OH
H H
NNH2
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ICSYNTH Strategy Parameters
• Rating of generated precursors/products
• Strategy: defined by a set of parameters
• 42 parameters (Retrosynthesis / FRP)
O OH
Reactant
Transform
Product(s)
ICSYNTH FRP Parameters
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Strategy Parameters Optimization
42 parameters (reactant, transform, product)
optimization algorithm
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Reactivity Mapping
FG Library Design
Ring Introduction
Scaffold Modification: Not Scaffold Hopping!!
ICSYNTH FRP Strategies
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FRP Examples / Applications
Reactivity Mapping
N NH
N
N OO
N NH
N
N OO
R
N NH
N
N NO R
N NH
N
N OO
Hal
N N
N
N OO
ON NH
N
N OO
R
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FRP Examples / Applications
FG Library Design
N NH
N
OHO
reaction center
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Knowledge-based Compound Design
Other Databases
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Knowledge-based Drug Design
• One synthetic step (reliable?) • Novelty • Drug like
• Physicochemical properties • Lipinski
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HN
O N
S
OHO
O
Penicillin G
Example from J. Chem. Inf. Model., Vol. 49, No. 5, 2009, 1163-‐1184
Knowledge-based Drug Design inspired by “de novo design using reaction vectors”
Example 1
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HN
O N
S
OHO
O
Penicillin G
Example from J. Chem. Inf. Model., Vol. 49, No. 5, 2009, 1163-‐1184
HN
O N
S
OHO
O
Reaction Vectors
ICSYNTH FRP (precision Medium) ICSYNTH FRP (precision High)
Knowledge-based Drug Design inspired by “de novo design using reaction vectors”
Example 1
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Knowledge-based Drug Design Example 1
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• 30 suggested cpds from ICSYNTH vs 1000 cpds (Reaxys, penicillinG sss)
• Fingerprint similarities calculated (30000) • Identical compounds filtered off (similarity = 1) • Compounds with Tanimoto distance between 0.5-0.9
were selected • Synthetic data (ICSYNTH) available • Calculated med chem properties of new suggestions as
well as med chem properties of previously reported ones available for analysis
Knowledge-based Drug Design Example 1
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Example 2
N
Cl N
O
Knowledge-based Drug Design
Core Structure (Diazepam)
Reaxys search
214 reactions / products
N
Cl
F
N
ON
Cl
HOO
N
O
N OO
N
ON
Cl O
NHO
NH
N O
NCl…
100 suggestions
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Example 2
Knowledge-based Drug Design Processing Information
• 80 new reactions identified
• 10 Identical matches
• 8 suggested products with a Tanimoto
distance <0.2
• 2 abstraction errors (knime)
but… it’s not enough for compound design…
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Example 2 (part II)
N
Cl N
O
Knowledge-based Drug Design
Core Structure (Diazepam)
80 new suggested reactions/products
versus
Reaxys substructure search
2564 related compounds
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• Fingerprints calculated
• Identical compounds filtered off (Tanimoto = 1)
• 13 suggested products with a Tanimoto 0.7-0.9
• Physicochemical properties calculated and compared
Knowledge-based Drug Design Example 2 (part II)
New “suggested” molecules show similar properties to the known-ones
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Cl
O
NN
N
Cl
O
HNO
Intermediate* used for ICSynth FRP and Reaxys sss
* Not real precursor for the final molecule
• 61 suggestions ICSYNTH FRP (one synthetic step away from intermediate)
• 922 related compounds in the literature (Loxapine included)
• 6 new compounds with Tanimoto distance between 0.5-0.9 were suggested
Loxapine®
Knowledge-based Drug Design Example 3
O
N
R
Cl O
NN
Cl
ArZ
O
NNH
Cl
Ar
O
NX
Cl
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One more thing…
building synthetic confidence
filtering ICSYNTH cpds with low synthetic background • number of precedent reactions of the same type • precedent yield reported • level of similarity from the original reaction
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Summary
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ACKNOWLEDGMENTS
InfoChem Peter Loew Heinz Saller Christoph Oppawsky Mike Hutchings Hans Kraut Valentina Eigner-Pitto Josef Eiblmaier Ulf Frieske Stephanie North
Chemnotia Anders Bogevig Tobias Rein
THANK YOU