Genome-based drug design

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A critical factor in the design of effective drugs is the specificity of the drug/target interaction. In the case of genome-based drug design, the double helical structure of DNA provides three binding mode opportunities for potential ligands. These are (1) binding in the major groove, (2) binding in the minor groove, and (3) intercalation between nucleotide bases. The naturally occurring compounds, netropsin and distamycin, along with their synthetic derivatives, the lexitropsins, bind in the minor groove of duplex DNA. Netropsin and distamycin specifically bind to A/T-rich sequences, whereas lexitropsins may be designed to bind A/T- or G/G-rich segments. Netropsin forms a 1:1 drug:DNA complex, whereas distamycin may form either 1:1 or 2:1 drug:DNA complexes. Both netropsin and distamycin also bind to G-quadruplex DNA. A single netropsin binds to each of the four quadruplex grooves, resulting in a 4:1 netropsin:quadruplex DNA complex. Distamycin dimers bind to one quadruplex groove forming a 2:1 complex or to opposite grooves resulting in a 4:1 complex. Depending on the nucleotide sequence of the G-quadruplex structure, distamycin dimers may bind to the terminal planes of the quadruplex, also resulting in a 4:1 distamycin:quadruplex structure. Typically, lexitropsins are designed to fit into the minor groove as overlapping molecular dimers or as hairpin structures. Hairpin lexitropsins fold onto themselves; as a result, their binding in the minor groove resembles that of dimeric molecules. Since the fundamental DNA sequence reading feature of netropsin, distamycin, and the lexitropsins is the hydrophobic interaction of their pyrrole/imidazole rings with nearby nucleotide bases, strategies to enhance and extend this interaction have been critical in the design of new minor groove recognizing compounds.

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