3d database searching

8/2/2019 3D Database Searching

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3D Database Searching and

Scaffold Hopping


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Database Searching

Selection of compounds for testing

Generation of new ideas

Validation of proposed structuralrequirements for activity


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Lock-and-Key Principle

. . . the intimate contact between themolecules . . . is possible only with similargeometrical configurations. To use a picture, Iwould say that the enzyme and the substratemust fit together like a lock and key.

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

Receptor

Ligand


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3D Database Searching

Docking

Using the lock, find keys that fit

Pharmacophore Search

Look for keys with same features


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Outline

Database Building

2D-to-3D Conversion

Multi-Conformational Databases

Pharmacophoric Searches

Scaffold Databases

Scaffold Hopping


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Available Compound Collections

ACD

NCI

Maybridge

ZINC collection a comprehensive collection

of drug like molecules


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2D-to-3D Conversion

OH

NH

NH

SO

OH


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Fragmentation into Cyclic/Acyclic Parts

OH

NH

NH

S

O

OH

NH

S

O

O

N

S

NH

OH


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Ring Templates


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Joining the Fragments


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Conformational Flexibility

conformationalensemble

low-energyconformation


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Conformational Analysis

Systematic Search

high number of conformers:

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

conformers

Sampling Techniques

Molecular Dynamics, Distance Geometry, SimulatedAnnealing

Poling: Promoting Conformational Variation


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Protein-Ligand Interaction

O

OH

H3

N+O

O

hydrogen bonds

salt bridges

hydrophobe

interactions cation- interactions

metal complexes


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Pharmacophore

A pharmacophore is a specific spatial

arrangement of atoms or functional groupsrequired for a drug molecule to exert aparticular biological effect.

OH

OH

NH

OH

adrenaline

2 - 3

4 - 7.2

6 - 8


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Pharmacophore Elements

Hydrogen bond donors:

Hydrogen bond acceptors:

Hydrophobes:

Positive ionizable groups:

Negative ionizable groups:

O

H

N

O

H

N

O

H

O

N+

H

N

H

N N+

H

H

H

H

O

O


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Pharmacophore Searching

2 - 3

4 - 7.2

6 - 8

3DDatabase

14251druglike compounds

843search hits

7 CPU min


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Alignment of 2 Search Hits

OH

NH

NH

S

O

OH

OH

OH

NH

OH


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Scaffold Hopping

Breaking out of old series: no further optimization possible

patent issues

backup

O

N

O

OH

OH

New Scaffold

O

N

O

OH

OH

S

OH

OH

O

O

N


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Conventional Approaches

Similarity Searchuses overall similarity to retrieve structures

Pharmacophore Search

focuses on features important for receptor-

ligand interaction

S

OH

OH

O

O

N

O

O

F

O


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Scaffold Hopping

GoalFind similar scaffolds, not similar compounds

Approach

1) Generate a non-redundant database of scaffolds2) Store position and orientation of substitution sites3) Use orientation of substitution sites on the query to

identify new scaffolds

ExampleEstrogen antagonists


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Generating the Scaffolds Database

ACD

Organon

Drugs

Scaffolds

scaffoldextraction

canonization

conformational

analysis

R

R

O

R

R

R

N

R

R


22/24

Scaffold Extraction

S

R

R

R

S

R

R

O

R

S

R

R

R

S

OH

OH

O

O

N

ringsystem

scaffold

-scaffold

R R


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Searching the Database

3D query

Scaffolds

suggestedscaffolds

N

R

R

R

R


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Conclusions

3D Database Searching

as valuable tool for virtual screening

2D-to-3D Conversion

based on an automated assembly of fragmentsConformational Analysisto take into account molecular flexibility

Pharmacophores

comprise features essential for biological activityScaffold Hopping

focuses on similar spatial orientation of substituents

3d database searching

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