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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
Outline
Database Building
2D-to-3D Conversion Multi-Conformational Databases
2D-to-3D Conversion
HN HO S O N H OH
HN HO S O N H OH
HN HO
S N O
S O N H
Ring Templates
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
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
O H
O
N H
O
N H
Hydrophobes:
HH + N
H H N H N
+
Pharmacophore Searching
6-8 2-3 4 - 7.2
3D Database
7 CPU min
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
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
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