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Drug and Target : Lock and Key ?
Algorithms
Non-Ligands
Structure Based Ligand Design
HN
O
Docking Linking
Building
O
HN
? HN HN
O
? O
H ? O
H
? H
O O O
? S
O
HN
O
O
HN
H H
? O O
HN
O S
N O
H
O
Structure based drug design
Define Pharmacophore O Ligand O
H H Design H
O O O O
H
O
H
O O
O O O
O
O
DB Search
O O
O H
H H
Building Molecules at the Binding Site
Experimental
Information: The active
site can be identified
based on the position of
the ligand in the crystal
structures of the protein-
ligand complexes
Ligand
F
.
..
H N
N
O S
F
. . 3. Calculate the
transformation matrix
H N
..
N
O S
N
for the orientation.
F
H N
N
O S
H N
N
O S
H-bonds
binding site parameterised
from X-ray binding site
Exact Receptor Structure is not
always known
Receptor Mapping
R2 R1
7.5-8.5
Anionic site
6.5
* Focus of charge
Cavity for part of piperidine ring
2D Substructure searches
Connectivity
O
Virtual screening: Target structure based approaches
Protein-ligand docking
o The most promising route available for determining which
molecules are capable of fitting within the very strict
structural constraints of the receptor binding site and to
find structurally novel leads.
o The most valuable source of data for understanding the
nature of ligand binding in a given receptor
ADMET
Absorption
Distribution
Metabolism
Excretion
Toxicity
TRADITIONAL RATIONAL APPROACH:
APPROACH: (CADD)
Screening of natural Molecular generation using
compounds for biological activity. crystal data or by modeling
techniques.
Isolation and purification.
Strictly structural and
Determination of structure Mechanism based approaches using
Structure-Activity computational and experimental
Relationship (SAR). techniques
Deriving the bioactive conformer
Synthesis of analogs.
by conformational search.
Receptor Theories.
Superposition and alignment.
Design and Synthesis of novel Deriving the pharmacophoric
drug structures. pattern.
(We dont mean this is Receptor mapping.
irrational!?!)
Studying the ligand-receptor
interactions by docking.
QSAR.
Traditional Approach Rational Approach
CAUTION.