Design in 2D, model in 3D: live 3D pose generation from 2D sketches Paolo Tosco
Design in 2D, model in 3D:live 3D pose generation from 2D sketches
Paolo Tosco
© Cresset
> Description of the grow3D workflow
Outline
> Introduction to the project
> Application to a case study
> Conclusions and outlook
© Cresset
How nice would it be…
…to design a molecule in the 2D sketcher and see it grow sensibly within the binding site in the 3D viewport?
Magenta:co-crystallizedcelecoxib in theCOX-2 active site
Grey: growing3D design
© Cresset
How hard can it be?
> Start from a blank 2D sketcher canvas
© Cresset
How hard can it be?
> Start from a blank 2D sketcher canvas> sketch something
© Cresset
How hard can it be?
> Start from a blank 2D sketcher canvas> sketch something> the largest 2D fragment is popped to a 3D
conformation…
© Cresset
How hard can it be?
> Start from a blank 2D sketcher canvas> sketch something> the largest 2D fragment is popped to a 3D
conformation…> …and docked into the protein’s active site
© Cresset
How hard can it be?
> Start from a blank 2D sketcher canvas> sketch something> the largest 2D fragment is popped to a 3D
conformation…> …and docked into the protein’s active site> …or aligned against a reference using a
combination of 3D fields and shape
© Cresset
How hard can it be?
> Start from a blank 2D sketcher canvas> sketch something> the largest 2D fragment is popped to a 3D
conformation…> …and docked into the protein’s active site> …or aligned against a reference using a
combination of 3D fields and shape> using the protein as excluded volume (if
available)
© Cresset
How hard can it be?
> Start from a blank 2D sketcher canvas> sketch something> the largest 2D fragment is popped to a 3D
conformation…> …and docked into the protein’s active site> …or aligned against a reference using a
combination of 3D fields and shape> using the protein as excluded volume (if
available)> then the grow3D process begins
© Cresset
Outline
> Introduction to the project
> Application to a case study
> Conclusions and outlook
> Description of the grow3D workflow
© Cresset
A simple flow chart will help: start from blank
We’ll keep it simple and start from a single fragment added to a blank 2D canvas
Look at disconnected fragments which
make up the sketch
YES
NO
Has the number of 2D
frags changed?
NO
YES Has the number of2D frags
increased?
No fragments
NH
N
© Cresset
A simple flow chart will help: generate 3D or grow3D?
Has the number of2D frags
increased?
Bonds/atomswere deleted
NO
N H 2
N
NH
N +
Has thetotal number
of atoms increased?
YES
No fragments
NH
N
Generate 3D structure for the
new 2D frag
YES
No atoms
NH
N
Frags were combined or deleted
NO
N H 2
N
NH
N+ or N
N H 2
Has the number of2D frags
changed?
Dock into binding siteor align to reference
grow3DNO
N
N
NH
N
© Cresset
Initial placement of the 3D design in the 3LN1 pocket
Co-crystallizedcelecoxib(magenta)
Aligned 3-methyl-pyrazole (grey)
© Cresset
A simple flow chart will help: growing the 2D design
Map current 2D frags to previous 2D frags
NO
No action
Loop over 2D frags: does this frag have 3D
coords?
N
N
NH
N
YES Pair current frag 2D indices
to previous
Compare# indices of current frag
with previous
Let’s add a methyl group in position 1 on the pyrazolesystem
>
Atoms were added
N
N
<
Atoms were deleted
NH
N
=
Check: • Element• Bonds• Bond order/
hybridization• Formal charge• Stereo
NH
N
© Cresset
A simple flow chart will help: growing the 3D design
A methyl groupwas added
NH
N
N
N
• Find bonds to added atoms
• Delete those bonds and cap with hydrogens
C H 4
NH
N
N
N
+
Generate 3D coords for newly added 2D frag
C H 4 Align frag Hs with parent’s heavy atoms and vice versa
Ready for the next grow3D iteration!
Attach to parent with appropriate bond order
Methyl was easy, can I have more of those, please?
© Cresset
Align frag Hs with parent’s heavy atoms and vice versa
1
23
A simple flow chart will help: scoring 3D designs
A phenyl ringwas added
• Find bonds to added atoms
• Delete those bonds and cap with hydrogens
N
N
N
N
+
Generate 3D coords for newly added 2D frag
N
N
N
N
© Cresset
A simple flow chart will help: scoring 3D designs
Attach to parent with appropriate bond order
Spin around bond and score against reference
1
23Rank models by score and do a local optimization
Align frag Hs with parent’s heavy atoms and vice versa
• Find bonds to added atoms
• Delete those bonds and cap with hydrogens
N
N
N
N
+
Generate 3D coords for newly added 2D frag
N
N
N
N
C C
A phenyl ringwas added
© Cresset
The devil is in the details (1): symmetries
When adding am-isopropyl substituent in 2D, there are actually two symmetry-equivalent positions it might fit in 3D
Let’s add it onone side first…
© Cresset
The devil is in the details (1): symmetries
…and then onthe other side
When adding am-isopropyl substituent in 2D, there are actually two symmetry-equivalent positions it might fit in 3D
© Cresset
The devil is in the details (1): symmetries
No matter which side the isopropyl substituent is drawn in 2D, the grow3Dalgorithm chooses the one which fits the active site best
© Cresset
The devil is in the details (2): chemically invalid states
When we draw a sulfone-containing functional group in 2D, we tend to go through a number of chemically invalid states
© Cresset
The devil is in the details (2): chemically invalid states
When we draw a sulfone-containing functional group in 2D, we tend to go through a number of chemically invalid states
We draw a methyl…
© Cresset
The devil is in the details (2): chemically invalid states
When we draw a sulfone-containing functional group in 2D, we tend to go through a number of chemically invalid states
…then we keep adding methyl groups until we get to a t-butyl…
We draw a methyl…
© Cresset
The devil is in the details (2): chemically invalid states
When we draw a sulfone-containing functional group in 2D, we tend to go through a number of chemically invalid states
…then we add the double bonds…
…then we keep adding methyl groups until we get to a t-butyl…
We draw a methyl…
grow3D pauses,waiting for our next move
© Cresset
The devil is in the details (2): chemically invalid states
When we draw a sulfone-containing functional group in 2D, we tend to go through a number of chemically invalid states
…then we turn terminal methylenes into oxygens…
…then we add the double bonds…
…then we keep adding methyl groups until we get to a t-butyl…
We draw a methyl…
grow3D still patiently waiting for some decent chemistry
© Cresset
The devil is in the details (2): chemically invalid states
When we draw a sulfone-containing functional group in 2D, we tend to go through a number of chemically invalid states
…and only in the end we turn the central carbon into a sulfur
…then we turn terminal methylenes into oxygens…
…then we add the double bonds…
…then we keep adding methyl groups until we get to a t-butyl…
We draw a methyl…
grow3D applies the change
© Cresset
Outline
> Introduction to the project
> Description of the workflow
> Application to a case study
> Conclusions and outlook
© Cresset
A case study: CHK1 inhibitors
In 2018 AZ published an interesting scaffold morphing exercise on some Checkpoint 1 kinase (CHK1) inhibitors they had previously identified
© Cresset
A (very) quick introduction to CHK1
> CHK1 is a promising target to improve the therapeutic index of DNA-damaging anti-cancer agents
> DNA damage triggers CHK1 activation, which in turn arrests the cell cycle, thus allowing DNA repair to take place
> Inhibiting CHK1 abrogates the cell cycle arrest, causing apoptosis
> CHK1 inhibitors would thus sensitize tumour cells to the action of DNA-damaging drugs
© Cresset
TCU and TZQ leads
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)Thiophene carboxamide
urea (TCU)Clinical candidate
2Triazoloquinolone
(TZQ)
The carbonyl group interacts with the backbone N-H of Cys-87
The amino group interacts with the backbone C=O of Glu-85
3Thiophene carboxamide
urea (TCU)Matched pair with 1
Both 1 and 3 feature an intramolecular hydrogen bondwhich stabilizes the bioactive conformation
NO
NH
N N
N HNH
O
NH
ONH 2
S
© Cresset
Ring closure, ring opening
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)Thiophene carboxamide
urea (TCU)Clinical candidate
2Triazoloquinolone
(TZQ)
S
FNH 2 O
N
NHN H
44-Carboxamide
thienopyridine (4-CTP)
Ringclosure
Ringopening
NO
NH
N N
57-Carboxamide
thienopyridine (7-CTP)
Matched pairsN H
NH
N
ONH 2
SF
© Cresset
Ring closure in grow3D
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringclosure
Let’s see what grow3D can do about the ring closure of 1 to 4
I’ll use the 2YDJ PDB structure (CHK1 co-crystallized with 1) as a reference
© Cresset
Positioning the initial 3D structure
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringclosure
I’ll start by generating a 3D conformation of 1 and aligning it to the X-ray reference
In the background, multiple 3D conformations of 1 are generated, and the one with the highest field/shape similarity score to the reference is chosen
© Cresset
Scaffold morphing begins
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringclosure
Then I turn the carbonyl group into an imine…
© Cresset
Scaffold morphing begins
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringclosure
…now the difficult bit: ring closure! (holding my breath)…
Then I turn the carbonyl group into an imine…
…the urea into an N-methylurea…
© Cresset
Scaffold morphing begins
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringclosure
Then I turn the carbonyl group into an imine…
…the urea into an N-methylurea…
Whoa, that worked!
© Cresset
Scaffold morphing begins
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringclosure
Then I turn the carbonyl group into an imine…
…the urea into an N-methylurea…
…let’s clean it up a little bit (both 2D and 3D)…
© Cresset
Scaffold morphing begins
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringclosure
Then I turn the carbonyl group into an imine…
…the urea into an N-methylurea…
…let’s clean it up a little bit (both 2D and 3D)…
…now I turn the dihydropyrimidineinto a dihydropyridine…
© Cresset
Scaffold morphing: done!
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringclosure
Then I turn the carbonyl group into an imine…
…the urea into an N-methylurea…
…let’s clean it up a little bit (both 2D and 3D)…
…now I turn the dihydropyrimidineinto a dihydropyridine…
…and aromatize to pyridine: done!
© Cresset
More transformations at constant #atoms
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringflip
I will now flip the thiophene ringto turn 4 into 5 in 4 moves:
N HNH
N
ONH 2
SF
5 (7-CTP)
© Cresset
More transformations at constant #atoms
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringflip
I will now flip the thiophene ringto turn 4 into 5 in 4 moves:
1. Hydrogenate the thiophene…
5 (7-CTP)
N HNH
N
ONH 2
SF
© Cresset
More transformations at constant #atoms
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringflip
I will now flip the thiophene ringto turn 4 into 5 in 4 moves:
1. Hydrogenate the thiophene…
2. Turn it into a cyclopentene…
5 (7-CTP)
N HNH
N
ONH 2
SF
© Cresset
More transformations at constant #atoms
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringflip
I will now flip the thiophene ringto turn 4 into 5 in 4 moves:
5 (7-CTP)
1. Hydrogenate the thiophene…
2. Turn it into a cyclopentene…
3. Dehydrogenate cyclopentene…
N HNH
N
ONH 2
SF
© Cresset
More transformations at constant #atoms
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringflip
I will now flip the thiophene ringto turn 4 into 5 in 4 moves:
5 (7-CTP)
1. Hydrogenate the thiophene…
2. Turn it into a cyclopentene…
3. Dehydrogenate cyclopentene…
4. Turn cyclopentadiene intothiophene…
N HNH
N
ONH 2
SF
© Cresset
More transformations at constant #atoms
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringflip
I will now flip the thiophene ringto turn 4 into 5 in 4 moves:
5 (7-CTP)
1. Hydrogenate the thiophene…
2. Turn it into a cyclopentene…
3. Dehydrogenate cyclopentene…
4. Turn cyclopentadiene intothiophene…and clean it up
N HNH
N
ONH 2
SF
© Cresset
More transformations at constant #atoms: how did we do?
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringflip
This is how our designed 5compares against its experimental X-ray structure 6FC8
5 (7-CTP)
N HNH
N
ONH 2
SF
© Cresset
Ring opening in grow3D
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
Let’s try and get to 4 through a ring opening approach starting from 2
I’ll use the 2X8E PDB structure (CHK1 co-crystallized with 2) as a reference
NO
NH
N N
This morphing involves far more changes to the scaffold than the previous one
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
As previously, I start by aligning my 2D design to the X-ray reference
NO
NH
N N
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
As previously, I start by aligning my 2D design to the X-ray reference
NO
NH
N N
Then I cleave the hydrazide bond
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
As previously, I start by aligning my 2D design to the X-ray reference
NO
NH
N N
Then I cleave the hydrazide bond
Get rid of the imino substituent
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
As previously, I start by aligning my 2D design to the X-ray reference
NO
NH
N N
Then I cleave the hydrazide bond
Get rid of the imino substituent
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
As previously, I start by aligning my 2D design to the X-ray reference
NO
NH
N N
Then I cleave the hydrazide bond
Get rid of the imino substituent
Re-aromatize the system
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
As previously, I start by aligning my 2D design to the X-ray reference
NO
NH
N N
Then I cleave the hydrazide bond
Get rid of the imino substituent
Re-aromatize the system
Turn the naphthalene into an isoquinoline
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Then I cleave the hydrazide bond
Get rid of the imino substituent
Re-aromatize the system
Turn the naphthalene into an isoquinoline
Break the phenyl ring as I need to make it 5-term
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Get rid of the imino substituent
Re-aromatize the system
Turn the naphthalene into an isoquinoline
Break the phenyl ring as I need to make it 5-term
Close to a cyclopentadiene ring
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Re-aromatize the system
Turn the naphthalene into an isoquinoline
Break the phenyl ring as I need to make it 5-term
Close to a cyclopentadiene ring
Turn cyclopentadiene into thiophene
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Turn the naphthalene into an isoquinoline
Break the phenyl ring as I need to make it 5-term
Close to a cyclopentadiene ring
Turn cyclopentadiene into thiophene
Turn pyridine into benzene
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Break the phenyl ring as I need to make it 5-term
Close to a cyclopentadiene ring
Turn cyclopentadiene into thiophene
Turn pyridine into benzene
Add m-fluorine to benzene
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Close to a cyclopentadiene ring
Turn cyclopentadiene into thiophene
Turn pyridine into benzene
Add m-fluorine to benzene
Grow methyl into an ethyl
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Close to a cyclopentadiene ring
Turn cyclopentadiene into thiophene
Turn pyridine into benzene
Add m-fluorine to benzene
Grow methyl into an ethyl
Attach a cyclohexyl to the ethyl
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Turn cyclopentadiene into thiophene
Turn pyridine into benzene
Add m-fluorine to benzene
Grow methyl into an ethyl
Attach a cyclohexyl to the ethyl
Turn methylene into amino
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Turn pyridine into benzene
Add m-fluorine to benzene
Grow methyl into an ethyl
Attach a cyclohexyl to the ethyl
Turn methylene into amino
Turn cyclohexyl into 3-piperidyl
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
Add m-fluorine to benzene
Grow methyl into an ethyl
Attach a cyclohexyl to the ethyl
Turn methylene into amino
Turn cyclohexyl into 3-piperidyl
Final clean-up, and we’re done!
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
This is how our designed 4compares against the experimental X-ray structure of 1 (2YDJ)…
ONH 2
NH
N HNH
O
F
S
1 (AZD7762)
© Cresset
A more complicated design case
2 (TZQ)
S
FNH 2 O
N
NHN H
4 (4-CTP)
Ringopening
NO
NH
N N
…and against the experimental X-ray structure of its close analogue 5 (6FC8)
5 (7-CTP)
N HNH
N
ONH 2
SF
© Cresset
Outline
> Introduction to the project
> Description of the workflow
> Application to a case study
> Conclusions and outlook
© Cresset
Conclusions
> grow3D is an algorithm which aims at generating sensible 3D poses in response to edits to a 2D sketch
> Poses are scored against their ability to fit a binding site and/or mimic electrostatics and shape of a reference ligand
> The algorithm is enough quick and accurate to enable real time assessment of design ideas
© Cresset
The simple flow chart (to be continued)
Atoms were added• Find bonds to added atoms, note their
indices and delete them, re-adding H’s• Fragment curr frag• Loop over originated frags, find those with
identical size and 2D coordsto prev(parent)
Break the input mol into frags
Has the number of frags changed?
NO
Pair prev frag indices with identical 2D coords to currand copy across 3D coords (if any)
Does curr frag have more indices
than prev?
NO
Atoms were deleted• Delete bonds to deleted atoms
from 3D coords• Fix hybridization of previously
bonded atom if needed• Delete atoms from 3D coords
Does curr frag have less indices
than prev?
YES
Loop over curr frags Is frag 3D?
NO
No action on currfrag
YES
NO YES
Check: • Element• Bond order• Hybridization• Formal chargeApply change to 3D coords
Atoms were added• Find bonds to added
atoms, note their indices and delete them, re-adding H’s
• Fragment curr frag• Loop over originated
frags, find the one with identical size and 2D coords to prev(parent)
Loop over children frags
• Generate 3D coordsfor the child frag
• Merge child frag into parent, aligning child H’s with parent’s heavies and vice versa (underdetermined if only one bond was broken: rotational scan)
Is the child frag a single atom?
YES NOReplace parent H with child atom
Regenerate bonds to parent with correct bond order
Render 3D coords
Are there more frags?
Frags have been combined or deleted
Has the total number of atoms
changed?
NO Frags were combined
Loop over prev frags which were combined
Is any frag 3D?
No action on combined frag
NO
YES
Minimize grown frag 3D coords
YES
Has the total number of atoms
increased?
NO
YES
Does any of the parent frags have
3D coords?
NOYESGenerate 3D coordsfor parent frags if needed
YES
NO
YES Has the total number of atoms
increased?
YES
No action on newly added frag
NO
Bonds (and possibly atoms) were deleted
© Cresset
cressetgroup
Thank you foryour attention
Acknowledgments
@Cresset: James Foley, Harry Jubb, Mark Mackey, Tim Cheeseright
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