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Christopher Reynolds,Stephen Muggleton and Michael Sternberg
Bioinformatics and Computing DepartmentsImperial College London
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In silico lead discovery by integrating ligand
screening and chemical synthesis rules
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Synthetic space is intractableINDDEx – a logic-based drug-discovery toolVirtual reactionsEstimating the size of searchable synthetic spaceFiltering search spaceEstimating the power of the virtual reaction searchCase study of application to drug discoveryConclusion
Summary • • • • • • • •
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The size of small molecule spaceMost frequently given estimate for all possible small-
molecules is around 1060
Drug-like molecules estimated between 1014 and 1030 Synthetically accessible estimated at 1013
Several publications and presentations have given estimates between 1018 and 10200
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ZINC databaseZINC = Zinc Is Not CommercialPublically available, free-to-useZINC 12 contains the 3D structures of > 35 million
“purchasable” molecules.Divided into subsets of
fragment-like molecules,purchasable molecules,etc.
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Synthetic space is intractableINDDEx – a logic-based drug-discovery toolVirtual reactionsEstimating the size of searchable synthetic spaceFiltering search spaceEstimating the power of the virtual reaction searchCase study of application to drug discoveryConclusion
Summary • • • • • •
• •
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• Investigational Novel Drug Discovery by Example. • A proprietary technology that uses an algorithm
developed from Inductive Logic Programming for drug discovery.
• SVILP• Support Vector Inductive Logic Programming• Applies SV weighting to ILP rules
• This approach generates human-comprehensible weighted logical rules which describe what makes the molecules active.
INDDEx™
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Understandable rulesStandard programs:
Activity = 0.45 LogP + 0.5667 LUMO + 1.65 V
AB C D
7Å
Logic-based rules:In an active molecule Fragment A is 7Å from fragment B which is bondedto fragment C which is bonded to fragment D
?
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Example ILP rulesactive(A):- positive(A, B), Nsp2(A, C),
distance(A, B, C, 5.2, 0.5).
active(A):- phenyl(A, B), phenyl(A, C), distance(A, B, C, 0.0, 0.5).
Molecule is active if there is a positive charge centre and an sp2 orbital nitrogen atom 5.2 ± 0.5 Å apart.
Molecule is active if a phenyl ring is present.
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Fragmentation of molecules into substructure
Inductive Logic Programming
generates QSAR rules
Screen model against molecular
database
Novel hits
Observed activity
INDDEx process
Support Vector Machines turn
qualitative rules into quantitative model
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Directory of Useful DecoysBenchmarking dataset40 protein targetsDecoys:Actives = 30:1Decoys selected to be physicochemically close to the
actives, but different in structure.
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Enrichment Factors on screening the Directory of Useful Decoys
Enric
hmen
t fac
tor
EF1% EF0.1%
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Synthetic space is intractableINDDEx – a logic-based drug-discovery toolVirtual reactionsEstimating the size of searchable synthetic spaceFiltering search spaceEstimating the power of the virtual reaction searchCase study of application to drug discoveryConclusion
Summary • • • • • •
• •
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Carrying out a virtual reactionSimple Molecular Input Reaction Kinetic
String (SMIRKS).ChemAxon’s Reactor tool contains a
library of SMIRKS along with rules about what a molecule must be like to participate in the reaction (Pirok et al, J Chem Inf Model, 2006).
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C=[N,O] + C(H)(=C)[C,N,P,S] + >>
SMIRKS reaction[C:3]=[N,O:4] + [C:1]([H:2])(=[C:6])[C,N,P,S:5] + >>
H
O
R+ EWG R
OHEWG
3
4
3
41
65 5
6
1
Bayliss-Hillman Alkylation reaction
C(C[N,O]H)(=C)[C,N,P,S][C:1]([C:3][N,O:4][H:2])(=[C:6])[C,N,P,S:5]
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ChemAxon rulesCan exclude reactants, and give requirements for
reactivity.match(reactant(0), “C=[N,O,S]”)match(ratom(3), “O=C[C:1]=O”)matchcount(reactant(0), “[F,Cl,Br,I]”)==1charge(ratom(3), “aromaticsystem”) > 0.3
Also give data for yield which can be used to guide choice of reactions.
Easy to add new rules and data.
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Predicted molecule
+
ReactantsProductMinimised productInitial reactant Partner reactant
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Synthetic space is intractableINDDEx – a logic-based drug-discovery toolVirtual reactionsEstimating the size of searchable synthetic spaceFiltering search spaceEstimating the power of the virtual reaction searchCase study of application to drug discoveryConclusion
Summary • • • • • •
• •
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INDDEx with virtual reactions
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Virtual reactions open up search space~ 100 commonly used organic reactions.482,606 fragment-like molecules in ZINC
database.54 reactions incorporated so far into INDDEx
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Virtual reactions open up search spaceRandom ZINC molecules tested:
100 randomly selected ZINC molecules
100 2.28 27,227 53,450
Random testmolecules
Average reactionsper molecule
Reactant partners
Total productsper molecule
All ZINC
35 million purchasable molecules in ZINCTherefore potential space
= 35,000,000 × 53,450 products per molecule= 1.9 × 1012 molecules
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Synthetic space is intractableINDDEx – a logic-based drug-discovery toolVirtual reactionsEstimating the size of searchable synthetic spaceFiltering search spaceEstimating the power of the virtual reaction searchCase study of application to drug discoveryConclusion
Summary • • • • • • • •
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Filtering search spaceNeed to cut down search space.Partial Logical Rule Reactant Selection (PLoRRS) uses the
INDDEx logical rules without support vector weighting to give a score of the potential of a molecule to form active compounds one synthetic step away.
INDDEx takes the top 100 positive rules, and gives one point for any rule only half-filled.
Identifies molecules that might potentially have their logic-based rules fulfilled after undergoing a reaction.
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Synthetic space is intractableINDDEx – a logic-based drug-discovery toolVirtual reactionsEstimating the size of searchable synthetic spaceFiltering search spaceEstimating the power of the virtual reaction searchCase study of application to drug discoveryConclusion
Summary • • • • • • • •
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Similarity – Tanimoto Coefficient
Atoms Bonds Total
NA 30 33 63
NB 26 28 54
NAB 18 21 39
NAB
NA + NB - NAB
0.47 0.53 0.50
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BenchmarkingAim is to quantify how well virtual reactions and PLoRRS
filtering can explore synthetic space by identifying molecules that are active but would not be found by a search of an existing database.
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INDDEx SVILP model
PLoRRS matches
DUD target set of active ligands
Training set of 8randomly chosen molecules‑
Test set of remaining active compounds
SVILP matches
Virtual synthetic products
Virtual synthetic products
Pooled consensus virtual synthetic products
Check for similarity to held back test set‑
ZINC fragment database filtered to remove structures
similar to the test set
Evaluation
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BenchmarkingThe method was tested on all 40 target sets in the DUD
dataset.Virtual reactions, with PLoRRS filtering and used to
search virtual synthetic space of each targetTests also done using SVILP as selection method for initial
and partner reactantsSuccess judged by similarity of generated molecules to
known actives
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Virtual compounds similar to known actives for the COX-2 target
Max
imum
sim
ilarit
y to
a k
now
n ac
tive
not i
nclu
ded
in th
e tr
aini
ng s
et
With PLoRRS method
Without PLoRRS method
Consensus method
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Virtual compounds similar to known actives for the PPAR γ target
Max
imum
sim
ilarit
y to
a k
now
n ac
tive
not i
nclu
ded
in th
e tr
aini
ng s
et
With PLoRRS method
Without PLoRRS method
Consensus method
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Mann–Whitney U testThe one-tailed p values when comparing the performances of the ‑
methods using the Mann–Whitney U statistical testThese results indicate that using the consensus method is
preferential to using either method individually, as it results in either an increased number of retrievals or the same amount
SVILP rank 100 Consensus rank 100 SVILP rank 1000 Consensus rank 1000
PLoRRS rank 100 0.464 0.214
SVILP rank 100 0.203
PLoRRS rank 1000 0.283 0.152
SVILP rank 1000 0.039
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Amount of synthetic space explored
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Case studies of the virtual productsCOX-2 targetRanked 90th
ZINC04369096 ZINC21985593
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Heck reaction
Virtual product formed
Closest match in the held-back actives, ZINC03959950
Virtual product Most similar molecule in training data, ZINC03814740.
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Speed and timing testingTo produce a derivative, and calculate a predicted score
for it, takes 107ms.Assuming an average number of 53,450 products per
molecules, this gives a time of 5,727 seconds to explore a single molecule (95 minutes).
Tests were performed on an Intel i7-3820 CPU @ 3.60GHz, running on a single core, with all data reading/writing from a Samsung PM83 Solid state drive.
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Synthetic space is intractableINDDEx – a logic-based drug-discovery toolVirtual reactionsEstimating the size of searchable synthetic spaceFiltering search spaceEstimating the power of the virtual reaction searchCase study of application to drug discoveryConclusion
Summary • • • • • • • •
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Case study: SIRT2 inhibitionSIRT2 is NAD-dependent deacetylase
sirtuin-2.3 chains, each a domain.
Linked to Parkinson’s disease.
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Molecules found by in vitro tests to have some low activity against SIRT2
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• Predicted molecules docked against modelled SIRT2 protein structure using GOLD™
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SIRT2 results – ScreeningTraining data
8 active moleculesIC50 activities between 1.5 µM and 78 µM, but the best were
unselective8 molecules with best consensus INDDEx and docking scores
purchased and tested.All molecules were structurally distinct from training molecules.
Two molecules had activity. One had IC50 of 1.45 μM. As good as one of the training data molecules, selective for SIRT2 and chemically distinct.
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SIRT2 results – Screening
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SIRT2 results – Virtual reactionsScaled-down virtual reactions method
Two reactions~ 30 library side-chains~ 1000 possible products
Made 171 derivatives9 had an IC50 less than 1.5 µM The best had an IC50 of 0.39 µM
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Synthetic space is intractableINDDEx – a logic-based drug-discovery toolVirtual reactionsEstimating the size of searchable synthetic spaceFiltering search spaceEstimating the power of the virtual reaction searchCase study of application to drug discoveryConclusion
Summary • • • • • • • •
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ConclusionINDDEx is powerful screening method whose strength
lies in learning topological descriptors of multiple active compounds.
Applying virtual reactions allows the efficient search of synthetic space and can generate compounds similar to known actives.
Promising drug leads found for SIRT2 protein.
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ImageryWikimedia CommonsiStockPhoto®
FundingBBSRCEquinox Pharma
AcknowledgmentsMike SternbergStephen MuggletonAta AminiSuhail Islam
SIRT2 drug designPaolo Di FrusciaMatt FuchterEric Lam
Chemistry Development Kit
The 3DSIG organisersAll of you for listening
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Questions?