The Synthetically Accessible Virtual Inventory (SAVI) project is an international collaboration between partners in government laboratories, small companies, not-for-profits, and large corporations, to computationally generate a very large number of reliably and inexpensively synthesizable novel screening sample structures. SAVI handles reactions not by virtue of applying simple SMIRKS to a set of building blocks of unknown availability. It instead combines a set of transforms richly annotated with chemical context, coming from, or being newly developed in the mold of, the original LHASA project knowledgebase, with a set of highly annotated, reliably available, purchasable starting materials. These components are tied together for SAVI product generation with the chemoinformatics toolkit CACTVS with custom developments for this project. Each product is annotated with a number of computed properties seen as important in current drug design, including rules for identifying potentially reactive or promiscuous compounds. After having produced and made publicly available the first (beta) set of 283 million SAVI products annotated with proposed one-step syntheses, we will be reporting on the second full production run aimed at creating a database of one billion high-quality, easily synthesizable screening samples. We will present the current status, ongoing developments, as well as scientific and technical challenges of the project.

1. Chemical Biology Laboratory
Center for Cancer Research
National Cancer Institute
National Institutes of Health
Synthetically Accessible Virtual Inventory (SAVI) :
Reaction generation and handling at the
billion compound scale
Hitesh Patel, Yuri Pevzner, Wolf D. Ihlenfeldt, Marc Nicklaus

2. Idea of SAVI
2
What can I
make
easily,
reliably,
safely
and
cheaply?
Not in screening databases
Many steps and very
costly
Potentially unsafe
Syntheses often unsuccessful
$$$$
∉
Problems of de novo design

3. Goal of SAVI
3
Reactant
A
Reactant
B
SAVI
Product
you can buy the
starting materials
1-step
reaction
no exotic
equipment
or
dangerous
procedures
annotate them
with computed
properties
important for
CADD

4. SAVI components
4
CACTVS
Lhasa Ltd (UK), LHASA LLC (US)
Building Blocks Transforms
Chemoinformatics
engine
LHASA transforms written in CHMTRN/PATRAN

5. Reaction enumeration tools & libraries based on them
 REAL database – Enamine
• 145k building blocks X 120 transforms
• REAL Space Navigator: BioSolveIT
• http://www.enamine.net/index.php?option=com_content&task=view&id=254%3f
 CHIPMUNK dataset – TU Dortmund
• Hartenfeller1, Reaxys and multicomponent reactions
• http://www.ccb.tu-dortmund.de/koch
 Scaffold design – ChemPass
• https://www.chempassltd.com/synspace-general-scaffold-design
 Reactor – ChemAxon
• https://chemaxon.com/products/reactor
 Other in house tools in industry
• Proximal Lilly Collection
• Pfizer Global Virtual Library (PGVL)
• Boehringer Ingelheim - BI CLAIM
5
1. Hartenfeller M, Eberle M, Meier P, et al (2011) A
Collection of Robust Organic Synthesis Reactions
for In Silico Molecule Design. J Chem Inf Model
51:3093–3098. doi: 10.1021/ci200379p

6. CHMTRN/PATRAN transform example
6
DISCONNECTIVE
SUBGOAL*ALLOWED
BROKEN*BONDS BOND*5 BOND*8 BOND*1
...
IF CARBON ON ALPHA TO ATOM*1 OFFPATH THEN SAVE IT AS 1
KILL IF NOT ARYL ON SAVED*ATOM 1 AND:IF &
SAVED*ATOM 1 IS MULTIPLY BONDED
...Possible elimination.
...Would eliminate.
KILL IF WITHDRAWING BOND ON ATOM*6 OFFPATH
KILL IF WITHDRAWING BOND ON ATOM*8 OFFPATH
KILL IF AROMATIC BOND ON ATOM*6 OFFPATH
IF BOND*6 IS A FUSION BOND THEN SUBTRACT 10 AND*THEN KILL IF &
NOT IN A RING OF SIZE 6
SUBTRACT 10 IF SECONDARY*CENTRE ON SAVED*ATOM 1
SUBTRACT 10 IF TERTIARY*CENTRE ON SAVED*ATOM 1
...Steric hindrance.
IF FEWER THAN TWO HYDROGENS ON ATOM*3 THEN SUBTRACT 15
...Works best with acetoacetic ester.
SUBTRACT 10 IF NOT HYDROGEN ON ATOM*1
ADD 15 IF ARYL ON ALPHA TO ATOM*6 OFFPATH
ADD 10 IF ARYL ON ATOM*8 OFFPATH
...Higher yields.
IF THERE IS A FUNCTIONAL GROUP ON ATOM*5 THEN DESIGNATE &
IT AS PARTICIPATING
CONDITIONS SnCl4/25
ACTUAL*CONDITIONS 419: ZnCl2
....
BREAK BOND*5
BREAK BOND*8
SINGLE BOND*6
ATTACH A KETONE ON ATOM*7
ATTACH AN ALCOHOL ON ATOM*6
BOND*1 IS DEFINED*SYN TO BOND*4
...
TRANSFORM 1039
NAME Feist Synthesis of Pyrroles
REFERENCES
J. Org. Chem. [53], 2084 (1988);
D.M. McKinnon, Can. J. Chem. [43], 2628 (1965).
COOR
_______/
II II
II II ===> AR-COCH-C(H) + (H)C-NHC=CHCO2R
/ / I I
(AR) C N C OH CH3
END*REFERENCES
...
TYPICAL*YIELD POOR
RELIABILITY FAIR
REPUTATION FAIR
HOMOSELECTIVITY GOOD
HETEROSELECTIVITY FAIR
ORIENTATIONAL*SELECTIVITY FAIR
CONDITION*FLEXIBILITY FAIR
THERMODYNAMICS FAIR
1D*PATTERN
N%C(-C[FGNOT=LEAVING])%C(-
C[FGS=ESTER,KETONE,NITRILE,AMIDE])%
C[HETS=0;FGNOT=LEAVING]%C(-
C[FGNOT=ACID,LEAVING,XWITHDRAWING])%@1
2D*PATTERN
C COR,CHO,CN,COOR,CON H C COR,CHO,COOR,CN,CON H O
| | | | | | "
N%C%C%C%C%@1 => N-C=C C- -C
| | | |
C H OH C
END*PATTERNS

7. CHMTRN/PATRAN transforms: smarter than SMARTS
7
24
14
IF BOND*6 IS A FUSION BOND
THEN SUBTRACT 10
34
ADD 10 IF ARYL ON ATOM*8
6
7
8
IF BOND*6 IS A FUSION BOND THEN SUBTRACT 10 AND*THEN
KILL IF & NOT IN A RING OF SIZE 6
KILL IF WITHDRAWING BOND ON ATOM*6 OFFPATH
49
ADD 15 IF ARYL ON ALPHA TO ATOM*6
ADD 10 IF ARYL ON ATOM*8
24
IF BOND*6 IS A FUSION BOND
THEN SUBTRACT 10
ADD 10 IF ARYL ON ATOM*8

8. Workflow
8
Building
blocks Pattern matching
building blocks for each
transform
Transforms
reactant1
building blocks
reactant2
building blocks
Product(s)
Are
reactants
same as
input ?
Scored lhasa
reaction
Ignore the
reaction
Save product,
reaction and
reactants
Filter by mol. wt.,
possibility of getting
mixture
Is there a
scored
lhasa
reaction?
Skip the
product
Get retro-synthetically
scored reactions
Generate product
Based on pattern in
transform
Make reactant pairs
No
Yes
No
Yes
Reaction killed

9. First SAVI production run (2016)
9
• CHMTRN/PATRAN transform logic
disqualified 17% of reactions
• Unique products
Downloadable at: https://cactus.nci.nih.gov/download/savi_download/
377,474
building blocks
14
transforms X351,298,493
305,775,262
283,194,312

10. 10
Product property distributions
0
5
10
15
20
100
200
300
400
500
600
700
800
900
1000
>1000
Millions
Mol Wt.
Molecular weight
0
1
2
3
4
5 0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
>2000
Millions
USD/gm
Cost per gram (predicted based on unit price)
0
2
4
6
8
10
12
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Millions
Fraction of SP3 Carbons
Fraction of SP3 hybridized carbons

11. SAVI produces novel ring systems
Total novel SA rings/scaffolds created: 999
(1) Ertl et al., J. Med. Chem. 49, 4568–4573 (2006)
“Novel”: not found in CADD Group aggregated
database of 152 million structures
Simple Aromatic (SA) “Ertl type”(1) novel ring/scaffold systems
SA: Systems up to tricyclic, ≥ 1 aromatic ring, with hetero atoms O, N, S
containing the moieties:
Novelty confirmed in SciFinder, few examples:
11

12. 12
Annotations for drug design
 “Drug design” properties:
• RO5 violations, PAINS matches, fsp3, log P…
• All 275 Bruns & Watson rules1 - combined as a demerit
score
 Sigma catalog numbers and unit price of building blocks
 Proposed reaction
> <SAVI_BUILDING_BLOCK_A_ORDER_LINK>
http://www.aldrichmarketselect.com/listBrowser.asp?structure_id=65139341
> <SAVI_BUILDING_BLOCK_A_COST_GRAM>
482.0
1. Bruns RF, Watson IA (2012) Rules for identifying potentially reactive or promiscuous compounds. J Med Chem 55:9763–
9772. doi: 10.1021/jm301008n
> <SAVI_REACTION>
Paal-Knorr Pyrrole Synthesis
> <SAVI_LHASA_SCORE>
45
> <SAVI_PREDICTED_YIELD>
VERY*GOOD

13.  ~600k building blocks
 ~20 chemistries (~50 transforms) implemented
• 7 entirely new chemistries
• example of new chemistry: Suzuki-Miyaura coupling
13
Next version of SAVI
OH
/
Ar' - [Cl,Br,I] + Ar - B ====> Ar - Ar'
OH
Ar - I + HC#R ====> Ar - C#R'
Br R1 OH Ar R1
/ / /
C=C + Ar-B ====> C=C
R2 OH R2
Suzuki coupling of Chloro, Bromo, Iodo
Suzuki coupling of Alkenes
Suzuki coupling with Alkynes

14. 14
1 M
10 M
100 M
1 B
10 B
100 B
100 K
10 K
1 K
~100 Billion total possible pairs
Possible reactant pairs: >> 1 billion

15. 15
 To generate comparable number of products for each transform
 Select 1 billion truly “interesting” compounds from 100 billions
reactions
 What filter criteria? Possible:
• Molecular weight, QED score1 of products
• Availability, reliability, purity and price of BBs
• Strict scoring by SUBTRACT -> KILL
 How to handle possible mixtures of products
 Handling and representation of 1 billion reactions
Poster (P 62) - The need for comprehensive reaction handling in
SAVI and beyond, Marc Nicklaus
Challenges
1. Bickerton GR, Paolini G V, Besnard J, et al (2012) Quantifying the chemical beauty of drugs. Nat Chem 4:90–98. doi: 10.1038/nchem.1243

16. More and better annotations planned
16
Predicted reaction conditions
Determine if SAVI product is a mixture
Annotate with
possible targets
2nd step
[Na]N=[N+]=[N-]

17. Ongoing work
17
grow molecule
elsewhere
Preserve reactant’s
functional groups already
known binding to a target

18. Iterative cycle for improved & new transforms
18
New LHASA
transforms
Implement in
CACTVS
SAVI pilot runs
Manual
inspection by
synthetic
chemists and
CADD group
Prioritizing
updates and
improvements

19. 19
Future plans
 Stricter criteria or CADD property to qualify a
reaction: less “haystack”
 Develop web-based GUI
 Investigate multi-step reactions
 Combine with robotic chemistry

20. CADD Group
• Devendra Dhaked
• Victorien Delannee
CCR
• Nadya Tarasova
Leidos
• Raul Cachau
• Megan Peach
• Jeff Saxe
Elsevier
• Scott Hutton
• Matt Clark
InfoChem
• Hans Kraut
• Josef Eiblmaier
Merck KGaA
• Friedrich Rippmann
• Mireille Krier
• Tim Knehans
MilliporeSigma
• Bret Daniel
• Chad Hurwitz
• Subir Ghorai
• Daniel Boesch
• Shashi Jasty
Lhasa Limited, UK
• Philip Judson
• Martin Ott
LHASA LLC, U.S.
• Alan Long
• Alex Sukharevsky
Novartis
• Peter Ertl
National Institute of Chemistry, Slovenia
• Dušanka Janežič
• Janez Konc
20
Acknowledgements