predictive retrosynthesis in...hbz meeting june 2020 - scifinder-n predictive retrosynthesis created...
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PREDICTIVE RETROSYNTHESIS IN
Copyright 2020 American Chemical Society. All rights reserved.
Approach, methods and future directions
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Copyright 2020 American Chemical Society. All rights reserved.
Synthesis is a Bottleneck
Complex, iterative process
Expensive and time intensive
Requires resources with deep domain knowledge
CASD – a powerful ideation tool
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Main value:
• Leads to strategies and reaction steps I wouldn’t have otherwise considered
• Exposes chemistry I was not familiar with
• Allows me to be more innovative
Task Support:
• Finding synthetic routes for known and novel molecules
• Identifying alternatives to known routes
• First pass / brain storming
But also plenty of room for improvement...
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A 7-months perspective
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Phase I – Experimental only (June 2019)
Retrosynthesis in SciFindern
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LDH inhibitor
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Phase I – Experimental only (June 2019)
Retrosynthesis in SciFindern
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Phase I – Experimental only (June 2019)
Retrosynthesis in SciFindern
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Phase I – Experimental only (June 2019)
Retrosynthesis in SciFindern
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CONTROLLING THE SEARCH
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A targeted bond will be disconnected in the first step
Protected bonds are never disconnected
Control of rules
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Copyright 2020 American Chemical Society. All rights reserved.
Guiding Principles
Holistic user experience embedded in the
SciFindern platform
Automated rule generation
Continuous R&D of methods and knowledge
• Diversity of solutions• Thorough coverage of known
chemistry• Tight linkage between
predictions and experimental evidence
Quality of results
• Flexibility in guiding the search• Options to filter and sort
solutions• A component of a larger
research and discovery toolkit• Ease of use
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Copyright 2020 American Chemical Society. All rights reserved.
Rule Generation
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Identify the essence of reactions
Molecular Perception
DRIVEN BY ADVANCED CHEMICAL PERCEPTION
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RingsAromaticityFunctional groupsStereochemistrySymmetry
Reaction Perception
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Rule Components
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• Rules capture the essence of chemical reactions.
• The rules are described by substructures along with many properties associated with the bonds and atoms that capture the scope of the reaction
RulePrediction
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Generalization as Key for Novelty
Copyright 2020 American Chemical Society. All rights reserved.
Using perception to achieve accuracy during extrapolation
Chemical perception facilitates generalizations that can lead to more diverse and more comprehensive solutions sets
EWG
EWG
EWGEWG
EWG
EWG
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Rules and Supporting Examples
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Populating the rules with the full content leverages the full body of knowledge creates a coherence between predictions and evidence.
Scheme Number of Examples
500,000
` 500,000
1,000
<10
common
rare
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EVIDENCE FOR PREDICTED REACTIONS
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FURTHER INSIGHTS
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Rule Matching During Search
Copyright 2020 American Chemical Society. All rights reserved.
Amide formation from carboxylic acid and a primary amine:
A rule matches if:1. Its product substructure maps perfectly somewhere in the target molecule
2. All the atom and bond properties match as well
+
Retron
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Rule Application
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A transform is an inverted reaction rule:
The rule is a template for generating precursors:
++
Rule: Transform:
+
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The Search
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1. Is the molecule commercially available? If cheap enough, stop!
2. Is the molecule a product of known reactions?
3. Are there rules that match the molecule?
Repeat for all precursors until either:
- Reached cheap commercially available substances
- Reached the synthetic depth
$$$
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Solutions Ranking
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Scoring criteria:
• Complexity reduction
• Convergence
• synthetic efficiency: number of steps, yield
• atom efficiency (waste)
• starting material coverage
• Cost
• Evidence
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Personalized Scoring
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Personalized Scoring
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Personalized Scoring
Copyright 2020 American Chemical Society. All rights reserved.
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Stereoselectivity
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Predictive Stereoselectivity
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Predictive Stereoselectivity
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Comprehensive properties for atoms and bonds defining scope of method
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• Regioselectivity
• Synthesizability of molecules
• Smarter search algorithms
• Functional group interference
• Ranking methods
• Speed
• User experience
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Other Research Projects
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Main principles:
• Comprehensive, rich and accurate
• Leveraging the most current data
• Versatile and easy to use
• A facet of a complete discovery experience
• Continuously updated and improved
Retrosynthesis in SciFindern
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