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