Design of B-DNA cross-linking and sequence-reading molecules.
We report the design of hybrid molecules to bind in the minor groove of B-DNA, which combine DNA alkylating and cross-linking ability for increased chemotherapeutic efficacy, with sequence specificity, to minimize side effects. Optimal linkage geometries have been determined for the synthesis of bis-anthramycin and anthramycin-netropsin hybrid molecules. Earlier studies on linked drugs have typically been based on molecular mechanics calculations. This work, in contrast, uses the observed crystal structures of a netropsin/DNA complex and a new anthramycin/DNA complex to determine the exact spacing between two individual drugs when bound in the minor groove of B-DNA. Molecular linkers then are designed and tested between these two experimental positions, to form a chimeric or bis-linked compound molecule. A linked anthramycin-netropsin molecule has been designed specifically to target the polypurine tract second-strand primer site of the reverse transcriptase of HIV-1.
Walker
W L
WL
Molecular Biology Institute, University of California at Los Angeles 90095, USA.
Kopka
M L
ML
Filipowsky
M E
ME
Dickerson
R E
RE
Goodsell
D S
DS
D001483:Base Sequence; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry*; D015195:Drug Design; D008969:Molecular Sequence Data; D016364:Reading Frames
D003432:Cross-Linking Reagents; D004247:DNA