期刊
ACCOUNTS OF CHEMICAL RESEARCH
卷 42, 期 1, 页码 11-21出版社
AMER CHEMICAL SOC
DOI: 10.1021/ar800016q
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资金
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI064200] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM061587] Funding Source: NIH RePORTER
- NIAID NIH HHS [R01 AI064200-05, R01 AI064200] Funding Source: Medline
- NIGMS NIH HHS [R01 GM061587, R01 GM061587-07] Funding Source: Medline
Targeting the minor groove of DNA through binding to a small molecule has long been considered an important molecular-recognition strategy in biology. A wide range of synthetic heterocyclic molecules bind noncovalently in the minor groove of the double helix and are also effective against a number of human and animal diseases. A classic structural concept, the isohelicity principle, has guided much of this work: such heterocyclic molecules require a shape that complements the convex surface of the minor groove. Researchers have used this principle to design molecules that can read DNA sequences. This principle also predicts that molecules that lack the complementary shape requirement would only bind weakly to DNA. Recently, however, researchers have unexpectedly found that some essentially linear compounds, which do not have this feature, can have high DNA affinity. In this Account, we discuss an alternative recognition concept based on these new findings. We demonstrate that highly structured water molecules can play a key role in mediating between the ligand and DNA minor groove without loss of binding affinity. Combined structural and thermodynamic approaches to understanding the behavior of these molecules have shown that there are different categories of bound water in their DNA complexes. For example, application of this water-bridging concept to the phenylamidine platform has resulted in the discovery of molecules with high levels of biological activity and low nonspecific toxicity. Some of these molecules are now in advanced clinical trials.
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