Protein-protein interactions (PPI) are one of the next predominant classes of therapeutic targets. With about 130,000 binary PPI just in humans [1], the development of small molecule drugs targeting these systems represents a considerable challenge with unprecedented pharmaceutical and medical benefits. However, experimental screening techniques (e.g High throughput Screening – HTS) relying on conventional commercial chemical libraries, that usually allow chemists to identify innovative molecules, have clearly demonstrated their limits on PPI targets. Those difficulties are mainly due to the inadequacy of those chemical libraries that were historically designed for conventional targets such as G-­-Protein Coupled Receptors (GPCR) or enzymes but most importantly to our misunderstanding of the PPI chemical space. A paradigm shift is therefore essential in our way to design chemical libraries when aiming at PPI targets. Following this path, learning from the known successful examples of PPI modulation with small non-­-peptide inhibitors has been pinpoint as a critical step. This strategy should help to promote in a more systematic manner new chemical entities (NCE), and allow the scientific community to derive general trends such as sets of appropriate physicochemical properties and privileged chemotypes. To guide the chemists in addressing this issue, we have created iPPI-­-DB. In this database, we have so far collected the structures, the physicochemical characteristics, and the pharmacological data (biochemical and/or cellular binding data) of 1650 small non-­-peptide inhibitors across 13 families of PPI targets (v1.0 -­- February 2013). Those data are extracted from the literature and manually curated by experts. As an online service to the PPI community, we wanted to propose a user-­-friendly web interface to access iPPI-­-DB [2]. Thus, we have developed a web application that can be accessed by anyone from the website of our Inserm technological platform CDithem. The uniqueness of iPPI-­-DB resides in the combination of its manual curation and the nature of its querying and visualizing tools. The first way to query our database is by choosing pharmacological criteria such as the PPI target, the threshold for the activity of the compound and/or for some molecular descriptors’s thresholds (molecular weight, proportion of sp3 carbon, etc.). All compounds fulfilling the query criteria are displayed as a list with all annotated properties. Recently, we added the possibility for users to sketch their own molecule in an embedded Marvin Sketch applet and to submit this molecule as the query for iPPI-­-DB using a similarity search based on ECFP4 or FCFP4 fingerprints (powered by JChem v6.1). The results of such query are displayed similarly to those of pharmacological queries for the five most similar iPPI-­-DB compounds based on the type of fingerprints chosen by the user. These results are preceded by a reminder of the input molecule structure using

1. iPPI-­DB:
A
user-­friendly
web
application
to
query
a
database
of
protein-­protein
interactions
inhibitors
Céline
Labbé
Inserm
UMR-­‐S
973
–
MTi
CDithem
pla=orm
Paris
ChemAxon's
10th
European
User
Group
MeeHng
May
20th-­‐21st
2014

2. 30
people
Sorbonne
Paris
Cité
campus:
4
universi9es
+
4
Ins9tutes
in
Paris
120,000
students
12,000
scien9sts
in
Life
and
Health
Sciences
23
hospitals
and
12,000
hospital
beds
RPBS-­‐MTI
958
64-­‐Bits
CPU
core-­‐linux
computer
cluster
2x15
To
data
storage
facility
MTi
research
unit
&
CDithem
platform
Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
2/24
MTi
at
University
Paris
Diderot
www.mH.univ-­‐paris-­‐diderot.fr
www.CDithem.com

3. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
3/24
Ø
High
number
of
protein-­‐protein
interacHon
(PPI)
Ø
Involvement
in
various
diseases
(eg
cancer)
Ø
Importance
of
finding
modulators
of
PPI
for
therapeuHc
intervenHon
Why
studying
the
PPI
?

4. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
3/24
Ø
High
number
of
protein-­‐protein
interacHon
(PPI)
Ø
Involvement
in
various
diseases
(eg
cancer)
Ø
Importance
of
finding
modulators
of
PPI
for
therapeuHc
intervenHon
Ø
Usually
use
of
High
Throughput
Screening
(HTS)
Ø
Inadequacy
of
commercial
chemical
libraries
Ø
MisconcepHon
of
the
PPI
chemical
space
Why
studying
the
PPI
?

5. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
3/24
Ø
High
number
of
protein-­‐protein
interacHon
(PPI)
Ø
Involvement
in
various
diseases
(eg
cancer)
Ø
Importance
of
finding
modulators
of
PPI
for
therapeuHc
intervenHon
Ø
Strategy:
learning
from
successful
examples
•
data
collecHons
on
PPI
and
inhibitors
of
PPI
(iPPI)
•
characterizaHon
of
the
PPI
chemical
space
•
creaHon
of
PPI
focused
chemical
libraries
Ø
Usually
use
of
High
Throughput
Screening
(HTS)
Ø
Inadequacy
of
commercial
chemical
libraries
Ø
MisconcepHon
of
the
PPI
chemical
space
Why
studying
the
PPI
?

6. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
4/24
Existing
databases
Targets
Manual
data
curaHon
Contents
All
types
Chemical
structures
•
Chemical
structure
•
Physicochemical
characterisHcs
•
Pharmacological
data
No
of
PPI
target
-
-
ü
ü
X-­‐Ray
only
No
of
compounds
1,300,000
71
7,000
1,650
44
50
31
NA
•
Chemical
structure
•
Pharmacological
data
•
Cocrystallized
structure
•
Chemical
structure
•
Physicochemical
characterisHcs
•
Pharmacological
data
PPI
only
PPI
only
PPI
only
ü
ü
ü

7. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
5/24
iPPI-­‐DB:
what
type
of
informations
?
Compound
Biblio
PPI
/
Proteins
Test
AcHvity
Ø
Molecular
descriptors
Ø
Compounds
names
Ø
External
references
-­‐>
AlogP,
Molecular
Weight,
Fsp3…
-­‐>
IUPAC,
brand
name
Ø
Type
of
test
Ø Test
name
Ø
Type
of
acHvity
Ø
AcHvity
value
-­‐>
IC50,
EC50,
Kd,
Ki
Ø
Pubmed
ID
or
Wipo
ID
-­‐>
arHcle,
patent
Ø
Title
Ø
Journal
Ø
Year
of
publicaHon
Ø
Pair
of
protein
names
Ø
Uniprot
number
-­‐>
ELISA,
fluorescence
polarizaHon…
-­‐>
Biochemical
or
cellular
test

8. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
6/24
Ø
Source
•
Liierature
(PubMed),
world
patents
•
Manually
curated
by
a
medicinal
chemist
Ø
Criteria
•
AcHvity
:
IC50,
Ki,
Kd,
EC50
<
30
μM
•
Absence
of
reacHve
or
promiscuous-­‐associated
chemical
funcHons
•
Rule
out
pepHdes
(Absence
of
3
conHnuous
pepHde
bonds)
•
Rule
out
macrocycles
•
Degree
of
validaHon
of
the
target
•
Clarity
of
the
experimental
data
on
binding
Ø
Stats
iPPI-­‐DB:
criteria

9. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
7/24
iPPI-­‐DB:
some
numbers
695
527
277
349
122
73
303
40
24
11
8
5
1
460
326
277
268
119
73
46
40
17
10
8
5
1
0
200
400
600
800
MDM2-­‐like/p53
BCL2-­‐like/BAX
LFA/ICAM
XIAP/Smac
CD4/gp120
CD80/CD28
Bromodomain/histone
Beta-­‐catenin/TCF-­‐4
IL2/IL2R
E2/E1
Myc/max
LEDGF/IN
ZipA/osZ
Number
of
compounds
and
binding
data
per
PPI
target
No.
of
unique
compounds
No.
of
binding
data
0
1
2
3
4
5
6
7
8
9
Number
of
iPPI
in
clinical
trials
per
PPI
target
(from
MDDR
data)
Phase
II
Phase
I
Preclinic

10. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
8/24
iPPI-­‐DB:
some
numbers
2
40
245
3
7
1
1
24
95
15
18
3
31
14
4
74
0
50
100
150
200
250
300
Cellular
Tests
pXC50
≥
8
7
>
pXC50
≥
6
8
>
pXC50
≥
7
6
>
pXC50
pXC50
=
-­‐
log(XC50x10-­‐6)

11. iPPI-­‐DB:
the
web
application
Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
9/24
Ø
Provide
the
PPI
community
with
a
user-­‐friendly
online
interface
Ø
Facilitate
the
access
to
the
right
informaHon
•
user
defined
criteria
•
cross
referencing
the
annotated
data
Ø
Help
to
prioriHze
the
selecHon
of
privileged
chemotypes
and
physicochemical
properHes
Ø
Can
be
accessed
by
anyone
at
www.ippidb.cdithem.fr

12. Search
by
pharmacological
criteria
-­‐
Query
Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
10/24

13. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
10/24
Ø
Only
the
selecHon
of
a
PPI
target
is
mandatory
Search
by
pharmacological
criteria
-­‐
Query

14. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
10/24
Ø
Only
the
selecHon
of
a
PPI
target
is
mandatory
Ø
Only
the
test
and
acHvity
type
available
for
the
selected
PPI
target
are
proposed
in
the
drop-­‐down
menus
Search
by
pharmacological
criteria
-­‐
Query

15. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
10/24
Ø
Only
the
selecHon
of
a
PPI
target
is
mandatory
Ø
Only
the
test
and
acHvity
type
available
for
the
selected
PPI
target
are
proposed
in
the
drop-­‐down
menus
Ø
pXC50
:
eg
•
pIC50
=
-­‐
log(IC50x10-­‐6)
•
pKd
=
-­‐
log(Kdx10-­‐6)
or
Search
by
pharmacological
criteria
-­‐
Query

16. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
10/24
Ø
Only
the
selecHon
of
a
PPI
target
is
mandatory
Ø
Only
the
test
and
acHvity
type
available
for
the
selected
PPI
target
are
proposed
in
the
drop-­‐down
menus
Ø
pXC50
:
eg
•
pIC50
=
-­‐
log(IC50x10-­‐6)
•
pKd
=
-­‐
log(Kdx10-­‐6)
or
Search
by
pharmacological
criteria
-­‐
Query

17. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
10/24
Ø
Only
the
selecHon
of
a
PPI
target
is
mandatory
Ø
Only
the
test
and
acHvity
type
available
for
the
selected
PPI
target
are
proposed
in
the
drop-­‐down
menus
Ø
pXC50
:
eg
•
pIC50
=
-­‐
log(IC50x10-­‐6)
•
pKd
=
-­‐
log(Kdx10-­‐6)
Ø
Fsp3
=
or
No
of
Carbon
sp3
No
Total
of
Carbon
Search
by
pharmacological
criteria
-­‐
Query

18. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
11/24
Search
by
pharmacological
criteria
-­‐
Results

19. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
11/24
Search
by
pharmacological
criteria
-­‐
Results

20. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
11/24
Search
by
pharmacological
criteria
-­‐
Results

21. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
11/24
Search
by
pharmacological
criteria
-­‐
Results

22. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
11/24
Search
by
pharmacological
criteria
-­‐
Results

23. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
11/24
Search
by
pharmacological
criteria
-­‐
Results

24. The
compound
ID
Card
-­‐
Summary
Céline
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–
EUGM
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–
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2014
–
12/24

25. Céline
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–
EUGM
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–
Budapest
2014
–
12/24
The
compound
ID
Card
-­‐
Summary

26. Céline
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–
EUGM
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–
Budapest
2014
–
12/24
The
compound
ID
Card
-­‐
Summary

27. Céline
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–
EUGM
Chemaxon
–
Budapest
2014
–
12/24
The
compound
ID
Card
-­‐
Summary

28. Céline
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–
EUGM
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–
Budapest
2014
–
12/24
The
compound
ID
Card
-­‐
Summary

29. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
13/24
Ø
3
/
75
filter
:
rule
for
in
vivo
toxicity
from
Pfizer
The
compound
ID
Card
-­‐
Physicochemistry

30. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
13/24
Ø
3
/
75
filter
:
rule
for
in
vivo
toxicity
from
Pfizer
all
iPPI
descriptors'
values
should
be
ideally
within
the
blue
area
The
compound
ID
Card
-­‐
Physicochemistry

31. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
13/24
Ø
3
/
75
filter
:
rule
for
in
vivo
toxicity
from
Pfizer
all
iPPI
descriptors'
values
should
be
ideally
within
the
blue
area
PCA
:
Principal
Component
Analysis
The
compound
ID
Card
-­‐
Physicochemistry

32. Céline
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–
EUGM
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–
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2014
–
14/24
LE
:
Ligand
Efficiency
1.37
×
pXC50
No
Heavy
Atoms
LE
=
LLE
:
Lipophilic
Efficiency
LLE
=
pXC50
−
AlogP
The
compound
ID
Card
-­‐
Pharmacology

33. Céline
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–
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–
Budapest
2014
–
15/24
Ø
Annotated
from
MDDR
data
(march
2012)
Ø
FCFP:
FuncHonal-­‐Class
Fingerprints
Ø
Similarity
:
Tanimoto
index
between
two
fingerprints
really
dissimilar
molecules
0
1
same
molecules
The
compound
ID
Card
–
Drug
similarity

34. More
information
?
Céline
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2014
–
16/24
PMID:
23688585

35. Search
for
drug
candidates
Céline
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–
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2014
–
17/24

36. Céline
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–
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–
Budapest
2014
–
17/24
Search
for
drug
candidates

37. Céline
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–
Budapest
2014
–
18/24
Search
for
drug
candidates
-­‐
Query

38. Céline
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–
EUGM
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–
Budapest
2014
–
18/24
Search
for
drug
candidates
-­‐
Query

39. Céline
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–
EUGM
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–
Budapest
2014
–
19/24
Search
for
drug
candidates
-­‐
Results

40. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
19/24
Search
for
drug
candidates
-­‐
Results

41. Towards
the
next
version
of
the
web
app
Céline
Labbé
–
EUGM
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–
Budapest
2014
–
20/24
Log
in
Get
your
results
!

42. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
20/24
Log
in
Get
your
results
!
Towards
the
next
version
of
the
web
app

43. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
20/24
Log
in
Get
your
results
!
Towards
the
next
version
of
the
web
app

44. Search
by
chemical
similarity
-­‐
Query
Céline
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–
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–
Budapest
2014
–
21/24
Ø
Copy
/
paste
a
SMILES
Import
a
file
Sketch
your
molecule
or
or

45. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
21/24
Ø
Copy
/
paste
a
SMILES
Import
a
file
Sketch
your
molecule
Ø
Example
from
:
or
or
Nutlin-­‐1
(acHvity
on
MDM2)
Search
by
chemical
similarity
-­‐
Query

46. Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
21/24
Ø
Copy
/
paste
a
SMILES
Import
a
file
Sketch
your
molecule
Ø
Example
from
:
or
or
Nutlin-­‐1
(acHvity
on
MDM2)
Search
by
chemical
similarity
-­‐
Query

47. Céline
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–
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–
Budapest
2014
–
22/24
Search
by
chemical
similarity
-­‐
Results

48. Céline
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–
EUGM
Chemaxon
–
Budapest
2014
–
22/24
Search
by
chemical
similarity
-­‐
Results

49. Conclusions
Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
23/24
Ø
a
database
ü
manually
curated
by
experts
ü
containing
:
-
chemical
structures
-
physicochemical
properHes
-
pharmacological
data
iPPI-­‐DB

50. Conclusions
Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
23/24
Ø
a
database
ü
manually
curated
by
experts
ü
containing
:
-
chemical
structures
-
physicochemical
properHes
-
pharmacological
data
Ø
a
user-­‐friendly
web
applicaHon
ü
search
by
pharmacological
criteria
ü
search
by
chemical
similarity
ü
cross-­‐referencing
the
annotated
data
ü
intuiHve
visualizing
tools
iPPI-­‐DB

51. Conclusions
Céline
Labbé
–
EUGM
Chemaxon
–
Budapest
2014
–
23/24
Ø
a
database
ü
manually
curated
by
experts
ü
containing
:
-
chemical
structures
-
physicochemical
properHes
-
pharmacological
data
Ø
a
user-­‐friendly
web
applicaHon
ü
search
by
pharmacological
criteria
ü
search
by
chemical
similarity
ü
cross
referencing
the
annotated
data
ü
intuiHve
visualizing
tools
iPPI-­‐DB
Assist
chemists,
biologists
and
clinicians
to
design
more
raHonaly
the
next
generaHon
of
PPI
modulators

52. Acknowledgement
Céline
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–
EUGM
Chemaxon
–
Budapest
2014
–
24/24
Ø
Mélaine
Kuenemann
(PhD
Student)
Ø
David
Lagorce
(Engineer)
Ø
Maria
Miteva
(Team
Leader)
Ø
Olivier
Sperandio
(Senior
Researcher)
Ø
Bruno
Villoutreix
(Unit
director)
Ø
Judith
Elkaim
(former
member)
Ø
Guillaume
Laconde
(former
member)
Ø
Pauline
Raballand
(former
member)
Ø
Benoît
Déprez
(Experimentalist)
Ø
Jean-­‐Luc
Poyet
(Experimentalist)