DRUG TARGETS:

NUCLEIC ACIDS
DNA & RNA
T A
G
C
H
3
N NH
3
O
O
proflavine
sugar phosphate
backbone
N H
3
N NH
3
Proflavine
van der Waals interactions
Ionic interactions
T
DNA DOUBLE HELIX
T
A
G
C
A
T
C
G C
T A
A T
C G
A
T A
T A
TA
TA
T A
G C
C
T A
TA
A
G C
T
C G
C G
A T
A T
G
G
Example Proflavine (antibiotic)
Intercalating agents
Proposed interaction of camptothecin with DNA and topo I, based on: (from wikipedia)
Crystal Structures of Human Topoisomerase I in Covalent and Noncovalent Complexes with DNA
Science 6 March 1998: Vol. 279. no. 5356, pp. 1504 1513. DOI: 10.1126/science.279.5356.1504
Matthew R. Redinbo, * Lance Stewart, * Peter Kuhn, James J. Champoux, Wim G. J. Hol
Fluoroquinolones
Topoisomerase
enzyme
Four drug molecules are stacked in the bound complex
Bound to DNA and enzyme by hydrogen and ionic bonds
X
8
N
R
6
R
7
R
5
O
O
O
R
1
Region binding to DNA
Stacking domain
X
8
N
R
6
R
7
R
5
O
O
O
R
1
Region
binding
to enzyme
Region
binding
to enzyme
X
8
N
R
6
R
7
R
5
O
O
O
R
1
X
8
N
R
6
R
7
R
5
O
O
O
R
1
Region
binding
to enzyme
Region
binding
to enzyme
X
8
N
R
6
R
7
R
5
O
O
O
R
1
Interstrand cross linking Intrastrand cross linking
Cross linking
Nu
Nu
X X
Nu
Nu Nu
Nu
X X
Nu
Nu
Alkylating agents
Cytosine Guanine
N
N
NH
2
O R
HN
N
N
N
O
H
2
N
R
Normal base pairing
Alkylating agents
Thymine Alkylated guanine
N
NH
O
O
Me
R
N
N
N
N
HO
R
H
2
N
DRUG
Miscoding resulting from
alkylated nucleic acid
bases
Guanine prefers
keto tautomer
Abnormal base pairing.
Alkylated guanine prefers
enol tautomer
Crystal structure of double-stranded DNA containing the major adduct of the
anticancer drug cisplatin, Patricia M. Takahara, Amy C. Rosenzweig,
Christin A. Frederick, Stephen J. Lippard. Nature. 1995. Vol. 377, Iss. 6550;
p. 649.
Generates DNA diradical
DNA diradical reacts with oxygen
Results in chain cutting
enediyne
system
Calicheamicin g
1
I
Antitumour agent
O
OMe
I
CH
3
O
OH
MeO
HO
H
3
C
OMe
S
O
O
H
3
C
OH
O
N
H
O
H
3
C
HO
O
O
MeO
H
N
H
3
C
H
S
S
S
H
3
C
HO
O
NHCO
2
Me
Chain cutters
BLEOMYCIN A2 R = NHCH
2
CH
2
CH
2
SMe
2
BLEOMYCIN B2 R = NHCH
2
CH
2
CH
2
CH
2
NHC(NH
2
)=NH
Chain cutters
Oxidative Strand Scission of Nucleic Acids: Routes Initiated by Hydrogen Abstraction from the
Sugar Moiety, Chem. Rev., 1998, 98 (3), pp 10891108, DOI: 10.1021/cr960437i Wendy Knapp
Pogozelski

and Thomas D. Tullius*

Proposed H-4-Abstraction Pathway for DNA Strand Scission Mediated by Activated
BleomycinFe(II) under Anaerobic Conditions (adapted from Worth et al.
39
and Hecht
90
)
Normal replication
A
T
C
G
A
A
C
C
T
A OH
3'
DNA
template
Growing
chain
P G
P P
A
T
C
G
A
A
C
C
T
A
G OH
3'
DNA
template
Growing
chain
P
Drug
P P
Chain termination
A
T
C
G
A
A
C
C
T
A OH
3'
DNA
template
Growing
chain
A
T
C
G
A
A
C
C
T
A
Drug
Chain termination
DNA
template
Growing
chain
A
C
A
T
G
T
T
G
T
A
C
A
5'
3'
O
O
N
H
N
N
Me
N
O
H
N
Me
O
O
N
H
N
N
N
H
O
Me
O
N
H
N
O
H
N
Me
Me
H
Me
N
Me
N
H
O
N
O
Me
N
H
O
N
N
Me
H
N
N
Me
O
N
H
H
H
Py
Im
Hp
Py
Py
Py
Hp
Im
Linker
Arm
Arm
Antisense Therapy
m-RNA
antisense
molecule
Protein synthesis
U C A G A U G C A A
A G U C U A C G U U
A A U G A A G U
m-RNA
antisense
molecule
Structural Comparison
T7-RNA polymerase
Rifampin and Sorangicin bound to Taq RNA polymerase
Rifampin Sorangicin