Innovation vs Invention (in organic synthetic research) Fernando F Huerta www.inoutscience.com Alicante, January 8 th 2016
Innovation vs Invention(in organic synthetic research)
Fernando F Huerta
www.inoutscience.comAlicante, January 8th 2016
Innovation vs Invention(in organic synthetic research)
1. Innovation and Invention definitions
2. Innovation and/or Invention in organic chemistry
3. Breakthrough in organic chemistry research
4. Research in the 21st Century (The Ugly Truth)
Innovation vs Invention
”two great invents”
1. Innovation and Invention definitions
Innovation vs Invention
”innovation”
1. Innovation and Invention definitions
Innovation1. Innovation and Invention
definitions
Innovation is significant positive change
Scott Berkunhttp://scottberkun.com/2013/the-best-definition-of-innovation/
”Invention”
1. Innovation and Invention definitions
New scientific or technical idea, and the means of its embodiment or
accomplishment. To be patentable, an invention must be novel, have utility, and be
non-obvious. To be called an invention, an idea only needs to be proven as workable.
But to be called an innovation, it must also be replicable at an economical cost, and
must satisfy a specific need. That's why only a few inventions lead to innovations
because not all of them are economically feasible.
”Innovation”
what about organic chemistry?
Nils Löfgren and Bengt Lundqvist
Unorthodox medicinal chemistry practice
Lidocaine
2. Innovation and/or Invention in Organic Chemistry
… in organic chemistry
The Suzuki-Miyaura Cross Coupling Reaction
• 1979 First Suzuki & co (2) publications
• 1978 Negishi (alkynylboron)
• 1975 Dieck and Heck
h"p://www.nobelprize.org/nobel_prizes/chemistry/laureates/2010/advanced-chemistryprize2010.pdf
Akira Suzuki, Nobel Prize in Chemistry in 2010
Mechanism
2. Innovation and/or Invention in Organic Chemistry
… in organic chemistry
The Suzuki-Miyaura Cross Coupling Reaction
“10588 publications since 2010”
2. Innovation and/or Invention in Organic Chemistry
… in organic chemistry
… organic chemistry lives
in continuous innovation
2. Innovation and/or Invention in Organic Chemistry
… in organic chemistry
what is the most significant
positive change for you?
3. Breakthrough in organic chemistry research
3. Breakthrough in organic chemistry research
“no more spending hours oflooking into the chemical abstracts”
… a significant positive change
• Endless searching posibilities
• Really fast
• Direct access to the literature references
3. Breakthrough in organic chemistry research
Chemical Information Systems
• In 1960’s research began using computers to support chemistry
• Late 80’s computer aided synthesis design was more than just a name (LASHA)
• Towards the end of 20th Century became the boom of chemical databases
• From 2005 cheminformatics became a new tool to achieve “Innovation”
… a significant positive change3. Breakthrough in organic
chemistry research
How was it possible?
OO
H
C5H4O2
furan-2-carbaldehyde
furfural
In computer language molecules are represented in different ways
Chemical Information Systems3. Breakthrough in organic
chemistry research
O=C([H])C1=CC=CO1
HYBBIBNJHNGZAN-UHFFFAOYSA-N
smiles
InChi KeyOO
H
furfural Smiles, InChi, Smarts, Smarks, etc… are different ways to work with big number of molecules in an easy way
Chemical Information Systems3. Breakthrough in organic
chemistry research
Molfile
Databases use connection tables (e.g. Molfiles) and/or linear string annotation to store chemical information.
Chemical Information Systems3. Breakthrough in organic
chemistry research
Substructure search “breakthrough”
• Subgraph isomorphism (Graph theory)• Atom-by-atom search (ABAS)• Molecular Fingerprints
• Chemical Information Systems have contributed to organic chemistry innovation. Agreed?
• Nowadays organic chemistry is more about innovation
• What about organic chemistry research innovation?
Summary…Fernando F Huerta
www.inoutscience.com
Innovation in organic synthetic research21st Century Chemical Information Tools
Computer Aided Synthesis Design
Analytical platforms
Compound & Reaction Databases
Visualisation Tools (Med. Chem.)
Datawarrioropenmolecules.org
Innovation in organic synthetic researchAnalytical platforms • Big data analytical platform
• Not exclusive for chemistry
• It can be used for compounds or reactions
• Extremely flexible (applications)
• It’s an open source software (free)
Knime
4. Research in the 21st Century(The Ugly Truth)
Research in the 21st Century (The Ugly Truth)
• “in silico” research
• Outsourcing
1. Synthesis of 1000 unknown molecules
2. New synthesis of a knonw molecule
3. Design new molecules based on reactivity
4. Other applications
Chemical Information Systems support in:
organic chemistry research needs to adapt to the actual situation
1. Synthesis of 1000 unknown molecules
• Computers design
• Computers predict
• Computers rank
• We plan (“in silico”)
• They make (“outsourcing”)
no synthesis associated
(“in silico”)
4. Research in the 21st Century(The Ugly Truth)
2. Synthesis of 1000 unknown moleculesUp to 100 molecules can be uploaded
well documented references
not ordered (lack of query ID)
difficult to navigate through the hits
+--
4. Research in the 21st Century(The Ugly Truth)
1. Synthesis of 1000 unknown molecules
The solution:
4. Research in the 21st Century(The Ugly Truth)
VirtualLibrary
(1000’s of compounds)
Second reaction step
Compound families(similar synthesis)
Synthesis suggestions(based on literature)
Best suggestion(Ranking)
onesyntheBcstep(retrosynthesis)
Ranking Availability of starting materials
Example performed using Knime/ICSynth tools but other systems can be used
2. New Synthesis of a Known Molecule
a b
cd
dO
HOF
Br
O
Route “d”
O
OBr
O
4. Research in the 21st Century(The Ugly Truth)
2. New Synthesis of a Known Molecule
O
OBr
O
a b
cd
cOOH
BrO
Org. Process Res. Dev. 2015, 19 (2), pp357-368Route “c”
4. Research in the 21st Century(The Ugly Truth)
3. Design new molecules based on reactivity
• Computersdesign
• Computerspredict
• Computersrank
• Weplan(“insilico”)
• Theymake(“outsourcing”)
no synthesis associated
(“insilico”)
However…
4. Research in the 21st Century(The Ugly Truth)
3. Design new molecules based on reactivity
However…
4. Research in the 21st Century(The Ugly Truth)
3. Design new molecules based on reactivity
Protein
Binding
Site
Why Do Drugs Look Similar?
Activity, Selectivity, ADMET,..
Similar structural motif share similar properties(?)
Drug Design Paradigm
4. Research in the 21st Century(The Ugly Truth)
• Reaction-based design
• Computers predict
• Computers rank
• They make (“outsourcing”)
(“in silico”)
3. Design new molecules based on reactivity
In principle: faster design cycles could be achieved
4. Research in the 21st Century(The Ugly Truth)
The mission: Generate ”New” Diazepam analogues
N
Cl N
O
Core Structure(Diazepam)
Reaxys reaction search
214 reactions / products
Reaxys substructure search
2564 related compounds
We“only”haveto:
• FindsuitablereacBons• Calculatebiologicalsimilarity(e.g.fingerprints)• Selectnewmoleculesonly
3. Design new molecules based on reactivity4. Research in the 21st Century
(The Ugly Truth)
3. Design new molecules based on reactivity4. Research in the 21st Century
(The Ugly Truth)
Knime-ICSYNTH-ICFRP combination:
N
Cl N
O
VirtualLibrary
Generation(based on reactions)
2564 analogues(Reaxys)
214 products(Reaxys)
VirtualLibrary
(new compounds)
Medicinal Chemistry filters
New Compounds similar to Diazepam
N
Cl
F
N
O
N OO
N
ON
Cl O
N O
NCl… N
Cl
HOO
N
ONHO
NH
• One synthetic step at the time
• Based on 4.5M reactions
• Free choice of reactions and reagents
• Predictions calculated for known and new
compounds
3. Design new molecules based on reactivity4. Research in the 21st Century
(The Ugly Truth)
Knime-ICSYNTH-ICFRP combination:
N
Cl N
O
VirtualLibrary
Generation(based on reactions)
2564 analogues(Reaxys)
214 products(Reaxys)
VirtualLibrary
(new compounds)
Medicinal Chemistry filters
New Compounds similar to Diazepam
N
Cl
F
N
O
N OO
N
ON
Cl O
N O
NCl… N
Cl
HOO
N
ONHO
NH
• One synthetic step at the time
• Based on 4.5M reactions
• Free choice of reactions and reagents
• Predictions calculated for known and new
compounds
The Ugly Truth
New “suggested” molecules show similar properties to the known-ones
Knime-ICSYNTH-ICFRP combination:
CLint
permeability
N
Cl N
O
Diazepam
NNH
O
NNFO
O
Olaparib
3. Design new molecules based on reactivity4. Research in the 21st Century
(The Ugly Truth)
4. Other Applications
Methodology applications: Looking for retrons!!
How many natural products and/or molecules of interest could I synthesize using this methodology?
commerciallyavailable
1000’sof compounds
List of compounds of interest using a specific
chemical transformation
Option 1
Option 2
www.drugbank.cacontains >7000approved drugs List of drugs containing
the desired retron
4. Research in the 21st Century(The Ugly Truth)
4. Other Applications
Predicting reactions?
Ar-BY2 + Ar’-HalCatalyst
Base
Solvent
Temperature
Yield
Ar-Ar’
a typical Suzuki coupling Molecular properties prediction(not quantum mechanics)
• logP• Polar Surface Area• MW• pKa• Number of HBD• Number of HBA• Etc…
15000 Suzuki-coupling reactions database (from Reaxys)
Would it be possible to find any type of “non-obvious” correlation to predict (estimate) the outcome of a Suzuki coupling, based on the molecular properties of its starting materials?
…idea in progress!
4. Research in the 21st Century(The Ugly Truth)
questions?
• Organic chemistry is about innovation
• Exponential increase of chemical information (>75M
compounds, CAS)
• New challenges: “in silico” and “outsourcing”
• How do I plan my research?
Take home message
ACKNOWLEDGMENTS
THANK YOU