Privileged Substructures Revisited: Target Community-Selective Scaffolds

Jürgen BajorathLife Science InformaticsUniversity of Bonn

Privileged Substructures First postulated by Evans et al. in 1988 based on the observation that

many cholecystokinin antagonists contained conserved substructures not frequently seen in other active compounds

Since then the search for target class-privileged chemotypes has continued in medicinal chemistry

Generally accepted definition:- Recurrent fragments in ligands of a given target family- Selective at the family level, but not for individual targets

Evans BE et al. J. Med.Chem.1988, 31, 2235-2246

ON

N

N

O

R1

X

R2 ON

N

N

O

N

R1

R2

X

R3O

N

N

N

OR1

X

YO

N

N

N

R1

X

R2

Privileged Substructures Existence of truly target family-privileged substructures has

remained controversial

Intrinsic limitation: Search for privileged substructures has been based on frequency of occurrence analysis of pre-selected substructures

Often drawn conclusion: Substructure might occur with high frequency among ligands of a particular target family but also act on other families

Schnur DM et al. J. Med. Chem. 2006, 31, 2000-2009

Target Family Set # Compounds # Substructures

GPCR class A 21620 1190

Ligand gated ion channels 3792 297

Nuclear hormonereceptors (NHRs) 2176 121

Protein kinases 1079 101

Serine proteases 3015 323

Privileged SubstructuresAre target family-privileged substructures truly privileged?

Schnur DM et al. J. Med. Chem. 2006, 31, 2000-2009

Target FamilySubstructure Sets

Ligand sets

GPCR Ion channels NHRs Protein

kinases Serine proteases

Random cpd sets

GPCR class A - 26% 10% 11% 17% 46%

Ligand gated ion channels 47% - 15% 19% 92% 99%

Nuclear hormonereceptors (NHRs) 40% 30% - 17% 15% 45%

Protein kinases 48% 34% 16% - 20% 57%

Serine proteases 25% 11% 7% 91% - 37%

Privileged SubstructuresAre target family-privileged substructures truly privileged?

Changing the Analysis Concept Do molecular scaffolds exist that exclusively occur in

ligands of individual target families ?

- Bemis & Murcko framework (scaffold)- Large-scale distribution in target families

NN Peptidases

Kinases

GPCRs

...

Departing from frequency of occurrence analysis of pre-selected substructures

Systematic compound data mining taking all available activity annotations into account

Hierarchical Scaffolds

Bemis GW and Murcko MA. J. Med. Chem.1996, 39, 2887-2893

Compound

R-groups Framework

Ring System Linker

1

2 3

N

N+

N

O

N

Cl

Cl

O

Public Data Source - BindingDB BindingDB database:

- Public repository of activity information of small molecules

- ~31,000 compound entries with ~57,000 activity annotations

- 17,745 compounds active against human targets extracted

Analysis Strategy - Compound Sets Target pair sets:

- Active compounds are organized into target pair sets - A set contains all compounds active against two individual

targets (i.e. compounds might belong to multiple sets)

Binding DB target pair sets:- Sets obtained for 520 pairs of targets that share >= 5

compounds- 6,343 compounds active against 259 human targets

Pubchem confirmatory bioassays:- Only 3 relevant human target pairs meet the >= 5 compound

criterion

Compound-Based Target Network 520 target pairs are visualized in a network

representation

- Nodes: targets- Edges: target pair sets - Edge width: number of

shared compounds

Densely connected communities- 18 communities- >= 4 targets- Different target families

1 2 3 4

5 6

7 8

9 10 11 12 13 14 15 16 17 18

Ser/Thr kinases

Serine proteinases

Caspases

Tyrosine kinases

MMPs & CAs

Community-Selective Scaffolds 520 human target pair sets (6,343 BDB compounds; 259

targets); 18 target communities

206 community-selective scaffolds:- Exclusively act in a single community- With 5 - 45 compounds/scaffold (av. ~12) - Yielding 147 distinct carbon skeletons (topological

diversity)

Adding Selectivity Information For each compound active against a target pair, its target

selectivity (TS) is calculated as:

Compound |TS| values range from 0 to 6.86- 0: equal potency, no selectivity- 6.86: potency difference of nearly 7 orders of magnitude, i.e.

highly selective for one target over another

Selectivity profiles of scaffolds- Community-based- Target-based

BATS ii pKpK

Selectivity Profiles Community-based selectivity profile:

- For each scaffold found in a given communityAll corresponding compounds active against any target pair in

this community pooledMedian of their absolute TS values determined (median |TS|)

Target-based selectivity profile:- For each scaffold active against a given target

All corresponding compounds active against this target pooled Selectivity against any other target calculatedMedian of their TS values determined (median TS)

Community Selectivity of Scaffolds Scaffold / Community heat map:

- Columns: target communities- Rows: scaffolds- Color spectrum: median |TS|

Red: scaffold yields many compounds with different potency against individual targets

Yellow: scaffold does not yield selective compounds

Non-selective scaffolds- Occur in multiple communities

Community-selective scaffolds- Exclusively occur in one community

Target Selectivity of Scaffolds Scaffold / Target heat map:

- Columns: targets in a community- Rows: scaffolds- Cell: the scaffold represents >= 5

compounds active against the target

- Color spectrum: median TS Red (positive): more selective for the

target over others in the community Yellow (negative): more selective for

other members of the community

Target Selectivity of Scaffolds

Different scaffolds display same selectivity profile- e.g. Factor Xa/Thrombin

Scaffolds with no apparent target selectivity

Number of scaffolds per target varies- Factor Xa: 17; Thrombin: 18- Tryptase: 0; Hepsin: 0

Community 3: 16 serine proteases

Target Selectivity Ranking Community-selective scaffolds are ranked according to

median |TS|

5.2

0

1

2

111 scaffolds with target-selective tendency

37 scaffoldsat least half of compounds having >= 100-fold potency differences against >= 2 community targets

Community-Selective Scaffolds

DPP4

DPP8

CA1

CA5A

CA5BCA6CA4

CA9

CA2

CA14

CA12

CA7

CA3

N

98: 1.10

3: 4.03

NN

RankMedian |TS|

Color spectrum: median TS Red: high potential to yield target-selective compoundsYellow: low potential

Selectivity Searching (MDDR)Thrombin

FXa

N

R1

R3

N

R5

R2

N

R1

R3

N

R4

R6

R2

NN

Highly selective for FXa over other serine proteases

Caspase 7

Caspase 3

N

O

O

S

O

NO

O

N

O

O

S

O

NO

OI

N

O

O

S

O

NO

OF

F

N

O

O

S

O

NO

OF

F

N

O

O

S

O

NO

OF

F

F

Selectivity Searching

Inhibit both caspase 3 and 7 with nM potency; ~200-fold selective over caspases 1, 6, 8

Extending the Analysis: ChemblDB Recent public domain database: ChemblDB

- ~500,000 compounds with activity information- 32,848 compounds with high-confidence annotations

active against 671 human targets High-confidence activity annotations:

- Target confidence level: 9- Interaction type: D(irect)

ftp://ftp.ebi.ac.uk/pub/databases/chembl/latest/

- Active compounds (human targets)- Scaffolds- Network- Community-selective scaffolds- Topologically distinct scaffolds

ChemblDB vs. BindingDB Comparison at different levels

32,848

ChemblDB

17,745

BDB3,589

12,902

ChemblDB

6,291

BDB1,409

Compounds Scaffolds

- Active compounds (human targets)

- Scaffolds- Network- Community-selective scaffolds- Topologically distinct scaffolds

ChemblDB vs. BindingDB Comparison at different levels

BDB

CDB

shared targetsunique targets

tyrosine kinases

GPCRs

- Active compounds (human targets)- Scaffolds- Network- Community-selective scaffolds- Topologically distinct scaffolds

ChemblDB vs. BindingDB Comparison at different levels

311

ChemblDB

206

BDB34

227

ChemblDB

147

BDB85

Community-selective Topologically distinct

Community-Selective Scaffolds Distribution in drugs?

- DrugBank: 1,247 approved drugs with 726 unique scaffolds

- Only 11 overlap with 206 community-selective BDB scaffolds

- Community-selective scaffolds currently underrepresented in drugs; opportunities for further chemical exploration

Conclusions The existence of target class-privileged substructures has remained

controversial over the years

From putative privileged substructures to confirmed target community-selective scaffolds through systematic data mining

Community-seletive scaffolds are abundant and topologically diverse

A subset of community-selective scaffolds displays a notable tendency to produce compounds with different target selectivity

BDB and CDB contain complementary target and scaffold information

Acknowledgments

Ye Hu

Anne Mai Wassermann

Eugen Lounkine