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Drug Design:
optimizing target interactions
1.
2.
HBA
Ar (R)
..
O ..
H
..
Ar (R) O ..
HBA
Alcohol or Phenol
HBD
HBA
..
..
O
..
Ar (R) O ..
Methyl ether
Analogues
HBA
Ester
Amines
HBA
HBA
HBA
R .. R
N
R .. H
N
H .. H
N
R
3OAmine
R
2oAmine
R
1oAmine
HBD
HBD
HBD
HBD
HBD
N
R
N
R
HBD
H
+
N
R
R N R
R
H
Ionic bond
Binding Site
8
Good interaction
Aromatic ring
Flat hydrophobic binding region
Poor interaction
Cyclohexane
Flat hydrophobic binding region
R
Alkene
R
Flat hydrophobic binding region
9
X R
+
Alkyl halide
..
H2N
Alkylation
Target
Nucleophilic group
H
R N
Target
X
Good leaving
group
10
Drug Optimization:
Strategies in drug design
I-optimizing drug target inetractions
12
Drug Optimization:
Strategies in drug design
I-optimizing drug target inetractions
13
Oxamniquine (schistosomicides) is an
example of a drug designed by classical
methods.
H
N
HN
O2N
OH
Oxamniquine
17
Drug Design:
II-optimizing access to the target
1-Improvement of absorption:
Cl
N
N
O
Cl
Cl
Ticonazole
Increase Polarity
OH
O
F
Fluconazole
N
N
N
O
N
H
N
O
H
H2 N
NH
Benzamidine
O
PRO3112
NH2
Amidine
24
O
Carboxylic Acid
Drug
N
Drug
OH
N
N
5-substituted Tetrazole
27
II-Improving
metabolism:
I-Making drugs more resistant
to chemical and enzymatic
degradation
28
HS
N
H
H
N
CONHMe
D1927
30
O
H2 N
O CH2CH2
Procaine
N
H
CH2
Lidocaine
33
O
O
O
Megestrol acetate
O
34
Summary
Targeting Drugs
44
Targeting Drugs
Reducing toxicity
Reducing toxicity
50
Reducing toxicity
Summary
Prodrugs
Prodrugs
1.
2.
3.
4.
5.
6.
7.
54
Summary
Summary
Drug alliances
Drug alliances
60
Drug Development
2.
3.
The drug has to be synthesized in everincreasing quantities for testing and eventual
manufacture (this is known as chemical and
process development).
63
64
Phase IV studies are ongoing and monitor the longterm use of the drug in specific patients, as well as the
occurrence rare side effects.
65
67
Thanq
Thank you
69