3D Database Searching and Scaffold Hopping

Database Searching
Selection of compounds for testing Generation of new ideas Validation of proposed structural requirements for activity

Lock-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. Ligand

Receptor

3D Database Searching
Docking Using the lock, find keys that fit

Pharmacophore Search Look for keys with same features

Outline
Database Building
2D-to-3D Conversion Multi-Conformational Databases

Pharmacophoric Searches Scaffold Databases Scaffold Hopping

Available Compound Collections

ACD NCI Maybridge ZINC collection a comprehensive collection of drug like molecules

2D-to-3D Conversion
HN HO S O N H OH

Fragmentation into Cyclic/Acyclic Parts

HN HO S O N H OH

HN HO

S N O

S O N H

Ring Templates

Joining the Fragments

Conformational Flexibility

low-energy conformation

conformational ensemble

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, Simulated Annealing

Poling: Promoting Conformational Variation

Protein-Ligand Interaction
hydrogen bonds salt bridges hydrophobe interactions cation- interactions metal complexes

O
H

O
O

H3N+

Pharmacophore
A pharmacophore is a specific spatial arrangement of atoms or functional groups required for a drug molecule to exert a particular biological effect.
OH
6-8 2-3 4 - 7.2

HO H N OH

adrenaline

Pharmacophore Elements
O

Hydrogen bond donors:

O H
O

N H
O

Hydrogen bond acceptors:

N H

Hydrophobes:
HH + N
H H N H N
+

Positive ionizable groups:

N
O O

Negative ionizable groups:

Pharmacophore Searching
6-8 2-3 4 - 7.2

3D Database

7 CPU min

14251 druglike compounds

843 search hits

Alignment of 2 Search Hits

OH HO H N OH

HN HO S O N H OH

Scaffold Hopping
Breaking out of old series: no further optimization possible patent issues backup
N O O

N O O OH

New Scaffold
OH

HO

HO

Conventional Approaches
Similarity Search uses overall similarity to retrieve structures Pharmacophore Search focuses on features important for receptorligand interaction
N O O

O O O

OH HO S

Scaffold 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

Generating the Scaffolds Database

R

Drugs
R

scaffold extraction
ACD

R N

conformational
Scaffolds

canonization
R
O R

analysis

Organon
R

Scaffold Extraction
R R
N O O
R

ringsystem
R R

scaffold
R

OH HO S

R O

-scaffold

R R S

Searching the Database

Scaffolds

3D query
R

suggested scaffolds

N R R R

Conclusions
3D Database Searching as valuable tool for virtual screening 2D-to-3D Conversion based on an automated assembly of fragments Conformational Analysis to take into account molecular flexibility Pharmacophores comprise features essential for biological activity Scaffold Hopping focuses on similar spatial orientation of substituents