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A knowledge-based approach for reaction generation. Development, validation and applications Dimitar Hristozov, 04.06.2009. public reaction databases. commercial reaction databases. Motivation. wealth of reaction data extract some of the knowledge hidden in these data

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a knowledge based approach for reaction generation

A knowledge-based approach for reaction generation

Development, validation and applications

Dimitar Hristozov, 04.06.2009

motivation

public

reaction

databases

commercial

reaction

databases

Motivation
  • wealth of reaction data
    • extract some of the knowledge hidden in these data
    • use this knowledge to assist the medicinal chemist
    • suggest new, synthetically feasible molecules with desired bio profile

lab notebooks (eLN)

medicinal chemists

U

>1,500,000 reactions covering general organic chemistry

large number of reactions per year, strong medicinal chemistry bias

proprietary

reaction

databases

public data

reaction vectors
Reaction vectors

From reaction database to knowledge base

R1

R2

P

reactant vector, R = (R1 + R2)

product vector, P

1

1

1

2

2

2

3

3

3

4

4

4

Bond

Bond

Bond

C-C

C-C

C-C

C=O

C=O

C=O

C-OH

C-OH

C-OH

C-OR

C-OR

C-OR

reaction vector, D = P - R

#

#

#

4

0

4

1

1

0

0

-2

2

0

2

2

Patel, H., Bodkin, M.J., Chen, B., Gillet, V.J.A Knowledge-Based Approach to De Novo Design Using Reaction Vectors, J. Chem. Inf. Model., 2009, ASAP article

from reaction vector to products i
From reaction vector to products (I)
  • The reaction vector, D, equals the difference between the product vector, P, and the reactant vector, R

D = P – R

  • Given a reaction vector, D, and a reactant vector, R, the product vector, P, can be obtained

P = D + R

  • Given a product vector, P, can we reconstruct the product molecule(s)?

better descriptor

is required

1

2

3

4

Bond

C-C

C=O

C-OH

C-OR

#

4

1

0

2

extended atom pairs
Extended atom pairs

atom types

atom pairs

n: number of bonds to heavy atoms

p: number of π bonds

r: number of ring memberships

AP2: atoms 1 bond away

AP3: atoms 2 bonds away

from reaction vector to products ii
From reaction vector to products (II)

“wrong” or “missing”

atom pairs

product vector (P = D + R)

C(2,1,0)-2(2)-O(1,1,0)

C(3,1,0)-2(1)-O(2,0,0)

C(3,0,0)-2(1)-O(2,0,0)

C(3,1,0)-2(1)-O(2,0,0)

reaction vectors in action
Reaction vectors in action

Reaction

APs “Lost”

APs “Gained”

Reaction Vector

C(2,0,0)-2(1)-O(1,0,0)

-1

C(2,1,0)-2(1)-C(2,0,0)

+1

C(2,0,0)-2(1)-C(2,0,0)

-2

C(2,1,0)-2(2)-C(1,1,0)

+1

Starting Molecule

Product

Atoms/bonds selected for removal using APs lost

New atoms/bonds added using APs gained

advantages
Advantages
  • Does not require manual atom-atom mapping of the reaction centre
  • Makes use of the synthetic chemistry data collected through the years
  • Accounts for the synthetic accessibility of the proposed molecules – all transformations are derived from successful reactions
  • Is fast to apply – no substructure searching is required
good approach
Good approach…

so how is it…

implemented?

optimisation made easy
Optimisation made easy
  • build as an Eclipse plug-in => 100% Java
looks great
Looks great…

but does it …

work?

reproducing reactions

1

create knowledge base

5,695

diverse

reactions

2,902

reaction

vectors

2

for each reaction

3

retrieve its reaction vector

-H2O

5

is the product obtained in less than 30 seconds?

4

apply the reaction vector to the starting materials

Reproducing reactions

+

how well did it work
How well did it work?
  • Products generated for ~90% of the 5,695 reactions
how fast did it work
How fast did it work?
  • Median run time: 0.015 seconds per reaction
epoxide reduction
Epoxide reduction

Epoxide reduction

  • reproduced in large variety of environments (350 reactions)
    • only one reaction was not reproduced
works like a charm
Works like a charm…

More than 95% reproduced successfully

epoxide reduction

epoxide formation

ester to amide

alcohol dehydration

acid to aldehyde

nitrile to aldehyde

Friedel-Crafts acylation

nitrile hyrdrolysis

alcohol amination

nitro reduction

aldol condensation

alkene oxidation

still works like a charm
Still works like a charm…

More than 90% reproduced successfully

olefin metathesis

amide reduction

ether halogenation

ozonolysis

Beckmann rearrangement

Claisen rearrangement

alkene halogenation

Dieckmann condensation

olefination

Wittig-Horner

Robinson annulation

claisen condensation
Claisen condensation
  • variety of environments were tested
  • 79 out of 100 reactions were successfully reproduced
  • 21% of the reactions were not reproduced
    • mainly condensations (intra- and intermolecular) which result in ring closures
still works
Still works

More than 50% reproduced successfully

  • A large variety of reactions successfully reproduced
  • Small difficulties with complex cycle formations
    • improvements are on their way

Cope rearrangement (67% success)

hetero Diels-Alder (73% success)

Claisen condensation (79% success)

Diels-Alder cycloaddition (49% success)

Fischer indole synthesis (57% success)

wow cool it works
Wow! Cool! It works!

but what is its…

use?

generating new molecules

Knowledge

base

Reagents

database

Generating new molecules

Starting molecule

Select reaction

transform

Is a second reagent

required?

yes

Select suitable

reagent

no

Can the transform

be applied?

no

Discard reaction

vector

yes

Apply reaction

transform

New molecule

slide30

Multi-objective de novo design

  • rank the proposed new molecules
  • direct the generation towards desired new molecules
use case one lead optimisation
Use case one: Lead optimisation

Here is my starting material. What kind of (feasible) one step transformations may I make?

  • starting molecule: Pencillin G

An example from Patel, H., Bodkin, M.J., Chen, B., Gillet, V.J. A Knowledge-Based Approach to De Novo Design Using Reaction Vectors, J. Chem. Inf. Model., 2009, ASAP article

lead optimisation cntd
Lead optimisation (cntd.)

Penicillin G

An example from Patel, H., Bodkin, M.J., Chen, B., Gillet, V.J. A Knowledge-Based Approach to De Novo Design Using Reaction Vectors, J. Chem. Inf. Model., 2009, ASAP article

use case two synthetic route
Use case two: Synthetic route

I have this (active) fragment. Is there a route from it to the molecule I have in mind?

  • reproducing known synthetic route – Plavix

1

2

3

4

Synthetic route from Wang, L. et al., Synthetic Improvements in the Preparation of Clopidogrel, Org. Process Res. Dev., 2007, 11 (3), 487-489

An example from Patel, H., Bodkin, M.J., Chen, B., Gillet, V.J. A Knowledge-Based Approach to De Novo Design Using Reaction Vectors, J. Chem. Inf. Model., 2009, ASAP article

use case three library design
Use case three: Library design

With which of these reagents will my starting material undergo reaction X?

  • enumerate a library using a single reaction and a number of different reagents

starting material

reaction X (X = Suzuki coupling)

628 boronic acids as reagents

An example from Patel, H., Bodkin, M.J., Chen, B., Gillet, V.J. A Knowledge-Based Approach to De Novo Design Using Reaction Vectors, J. Chem. Inf. Model., 2009, ASAP article

library design cntd
Library design (cntd.)

292 products generated

summary
Summary
  • The reaction vectors offer good way to explore the knowledge hidden inside reaction databases
  • A variety of chemical reactions can be reproduced with this approach
  • The method works fast
  • The is applicable in different medicinal chemistry related scenarios
  • The use of the method is made easy by variety of KNIME nodes which have been implemented
acknowledgements
Acknowledgements
  • Michael Bodkin
    • for his continuous support both in and outside my daily work
  • Hina Patel
    • for creating the first prototype which sprung the reaction vectors into live (http://pubs.acs.org/doi/abs/10.1021/ci800413m)
  • Dave Evans, Fred Ludlow, Swanand Gore, Dave Thorner, Maria Whatton, Juliette Pradon
    • for many stimulating discussions and for their continuous support
thank you
Thank You!

do you have any…

questions, comments, recommendations?