M. Wagener

3D Database Searching and 3D Database Searching and Scaffold HoppingScaffold Hopping

Markus Wagener

NV Organon

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Database SearchingDatabase Searching

• Selection of compounds for testing

• Generation of new ideas

• Validation of proposed structural requirements for activity

M. Wagener

Lock-and-Key PrincipleLock-and-Key Principle

‘‘. . . the intimate contact between the molecules . . . is possible only with similar geometrical configurations. To use a picture, I would say that the enzyme and the substrate must fit together like a lock and key.’’

Emil Fischer, Ber. Dtsch. Chem. Ges. 1894, 27, 2985.

Receptor

Ligand

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3D Database Searching3D Database Searching

Docking

Using the lock, find keys that fit

Pharmacophore Search

Look for keys with same features

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OutlineOutline

• Database Building– 2D-to-3D Conversion– Multi-Conformational Databases

• Pharmacophoric Searches

• Scaffold Databases

• Scaffold Hopping

M. Wagener

Available Compound CollectionsAvailable Compound Collections

0

50

100

150

200

250

300

350

400

in house ACD WDI NCI Maybridge Specs

Siz

e x

100

0

http://cactus.nci.nih.gov/ncidb2/

M. Wagener

2D-to-3D Conversion: Corina2D-to-3D Conversion: Corina

OH

NH

NH

SO

OH

J. Sadowski, J. Gasteiger Chem. Rev. 1993, 93, 2567.

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Fragmentation into Cyclic/Acyclic Parts Fragmentation into Cyclic/Acyclic Parts

OH

NH

NH

SO

OH

NH

SO

O

N

S

NH

OH

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Ring TemplatesRing Templates

27 kJ/Mol

50 kJ/Mol

56 kJ/Mol

18 kJ/Mol

25 kJ/Mol

43 kJ/Mol

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Joining of Ring Templates: CubaneJoining of Ring Templates: Cubane

Ring 2 Ring 3 Ring 4 Ring 5

no conformationfor 3rd ring

Ring 1

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Joining the FragmentsJoining the Fragments

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Conformational FlexibilityConformational Flexibility

conformationalensemble

low-energyconformation

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Conformational AnalysisConformational Analysis

• Systematic Search

– high number of conformers:

e.g. 10 rotatable bonds with 120º steps: 310 ~ 60,000

conformers

• Sampling Techniques

– Molecular Dynamics, Distance Geometry, Simulated

Annealing

• Poling: Promoting Conformational Variation

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Conformational FlexibilityConformational Flexibility

0

5

10

15

20

25

30

0 60 120 180 240 300 360

Ene

rgy

[kJ/

Mol

]

Torsion Angle

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Conformational PolingConformational Poling

A. Smellie, S.L. Teig, P. Towbin J. Comp. Chem. 1995, 16, 171.

Conformational Coordinate

Ene

rgy

+ Epole

Energy =

Ebond

+ Eangle

+ Edihedral

+ Enonbonding

C3 C2

C1

M. Wagener

Lock-and-Key PrincipleLock-and-Key Principle

‘‘. . . the intimate contact between the molecules . . . is possible only with similar geometrical configurations. To use a picture, I would say that the enzyme and the substrate must fit together like a lock and key.’’

Emil Fischer, 1891

Receptor

Ligand

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Protein-Ligand InteractionProtein-Ligand Interaction

O

OH

H3N+O

O

• hydrogen bonds• salt bridges• hydrophobe

interactions• cation-π interactions• metal complexes

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Pharmacophore DefinitionPharmacophore Definition

A pharmacophore is a specific spatial arrangement of atoms or functional groups required for a drug molecule to exert a particular biological effect.

OH

OHNH

OH

adrenaline

2 - 3 Å

4 - 7.2 Å

6 - 8 Å

adapted from: C.D. Strader et al. J. Biol. Chem. 1989, 264, 13572.

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Pharmacophore ElementsPharmacophore Elements

Hydrogen bond donors:

Hydrogen bond acceptors:

Hydrophobes:

Positive ionizable groups:

Negative ionizable groups:O

O

N+

H

N

H

N

O

H

O

H

O

N

O

H

N N+

H

H

H

H

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Pharmacophore SearchingPharmacophore Searching

2 - 3 Å

4 - 7.2 Å

6 - 8 Å

3DDatabase

14251druglike compounds

843search hits

7 CPU min

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Alignment of 2 Search Hits Alignment of 2 Search Hits

OH

NH

NH

SO

OH

OH

OHNH

OH

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Quality of the PharmacophoreQuality of the Pharmacophore

• Adrenergic agonists:

Hitsactive / Hitstotal

DBactive / DBtotal

EF = = 7.049 / 843

119 / 14251=

Hitsactive / Hitstotal

DBactive / DBtotal

EF = = 4.341 / 843

162 / 14251=

• Dopaminic Agonists:

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O

N

O

OH

OH

New Scaffold

O

N

O

OH

OH

SOH

OH

O

O

N

SOH

OH

O

O

N

Scaffold HoppingScaffold Hopping

Breaking out of old series:

• no further optimization possible

• patent issues

• backup

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O

O

F

O

Conventional ApproachesConventional Approaches

Similarity Search

uses overall similarity to retrieve structures

Pharmacophore Search

focuses on features important for receptor-ligand

interaction

SOH

OH

O

O

N

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Scaffold HoppingScaffold Hopping

Goal

Find similar scaffolds, not similar compounds

Approach

1) Generate a non-redundant database of scaffolds

2) Store position and orientation of substitution

sites

3) Use orientation of substitution sites on the query

to identify new scaffolds

Example

Estrogen antagonists

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Generating the Scaffolds DatabaseGenerating the Scaffolds Database

ACD

Organon

Drugs

Scaffolds

scaffoldextraction

canonization

conformational

analysis

R

R

O

R

R

R

N

R

R

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Scaffold ExtractionScaffold Extraction

SR

R

R

SR

R

O

R

SR

R

R

SOH

OH

O

O

N

ringsystem

scaffold

π-scaffold

R R

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Searching the DatabaseSearching the Database

3D query

Scaffolds

suggestedscaffolds

N

R

R

R

R

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raloxifene

substitution sites

+ aromatic ring

+ ring orientation

+ directions

3D query

+ shape

A Query for ER antagonistsA Query for ER antagonists

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Hits with the ER Antagonist QueryHits with the ER Antagonist Query

Scaffolds

1027 hits

631 π-scaffolds

364 scaffolds

261 ringsystems3D query

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Results: Matching the QueryResults: Matching the Query

LY-357489

OH

O

O

OH

N

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SRR

R

O R

RR

R

R

R

R

R

RR

R

R

O

R

R

SR

R

O

R

S

O

R

R

RN

R

R

R

R

OH

OHO

N

RU-39411

Other Scaffolds ...Other Scaffolds ...

SOHOH

O

N

LY-335124 O OH

OH

ON

EM-652OH

OH

ON

LY-326315

N

OH

O

OH

N

pipendoxifene

S

O

OH

O

O

N

arzoxifene

SOH

OH

O

ON

raloxifene

OH

O

O

OH

N

LY-357489

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ConclusionsConclusions

3D Database Searchingas valuable tool for virtual screening

2D-to-3D Conversion

based on an automated assembly of fragments

Conformational Analysisto take into account molecular flexibility

Pharmacophorescomprise features essential for biological activity

Scaffold Hoppingfocuses on similar spatial orientation of substituents

M. Wagener

Further ReadingFurther Reading

• A.C. Good, J.S. Mason Three-Dimensional Structure Database Searches. in: Reviews in Computational Chemistry, K.B. Lipkowitz, D.B. Boyd, Ed., VCH Publishers, 1996, 67-117.

• D.T. Manallack Getting that Hit: 3D Database Searching in Drug Discovery. Drug Disc. Today 1996, 1, 231-238.

• M.A. Miller Chemical Database Techniques in Drug Discovery. Nat. Rev. Drug Disc. 2002, 1, 220-227.

• H.J. Böhm, G. Klebe, H. Kubinyi Wirkstoffdesign. Spektrum Verlag, 1996.

available only in German, but really worth the effort.