pyrrole–amidine antibiotics(Figure 9.13) that have antibacterial and antiviral activity, presumably as a
result of their interaction with DNA. Both compounds have been the focus of much study as DNA
interactive ligands. These drugs have a binding preference forA T-rich minor groovesover G C-
containing sequences. The preferred binding site is 5 -AATT and to a lesser extent 5 -ATAT. The rather
similar sites 5 -TTAA and 5 -TATA are disfavoured sites of interaction. These differences in binding site
preference have been interpreted in terms of sequence-dependent variations in minor groove widthas
well as due to the disruption induced by the unusually flexible TpA base pair step. In general, these drugs
bind in a narrowed minor groove and the complex is stabilised by a combination of electrostatic inter-
actions between the DNA and the cationic end groups, as well as by hydrogen bonds to N-3 of adenines and
O-2 of thymines. In addition, non-bonded hydrophobic interactions are made with the sugar–phosphate
backbone that defines the walls of the groove. The binding site size of netropsin is about four consecutive
A T base pairs. Since distamycin is a longer molecule it requires at least five or six contiguous A T
base pairs.
9.7.2.1 Structures of Netropsin– and Distamycin–DNA Complexes. Dickerson and co-workers
solved the first X-ray crystal structure of a netropsin–DNA complex in 1985.^31 The DNA target was the
Dickerson–Drew dodecamer: d(CGCGAATTCGCG) 2 , referred to here as A2T2. As expected, netropsin
binds in the central AATT of the duplex and it displaces several water molecules that are present in the
drug-free structure. The three-ligand amide groups point inwards and form bifurcated or three-centred
hydrogen bonds with N-3 of adenine and O-2 of thymine. The netropsin fits tightly into the narrow minor
362 Chapter 9
Figure 9.13 Structures of some DNA minor groove binding ligands