Design of B‐DNA cross‐linking and sequence‐reading molecules

Walker, Wynn L.; Kopka, Mary L.; Filipowsky, Mark E.; Dickerson, Richard E.; Goodsell, David S.

doi:10.1002/bip.360350513

Cited by 19 publications

(15 citation statements)

References 28 publications

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“…These agents have also received considerable attention as DNA anchoring systems for nonspecific DNA cleaving agents such as Fe II −EDTA . Additionally, conjugation to the 5‘-AATT-3‘ minor groove binding agent netropsin has been pursued as a means of enhancing the specificity of DNA modification by anthramycin …”

Section: 83 Pyrrolobenzodiazepine Dimersmentioning

confidence: 99%

DNA Cross-Linking Agents as Antitumor Drugs

1998

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Section: 83 Pyrrolobenzodiazepine Dimersmentioning

confidence: 99%

DNA Cross-Linking Agents as Antitumor Drugs

1998

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“…netropsins or lexitropsins together via a short connecting chemical group or linker. Initial design of these linkers involved trial and error and chemical intuition, but for a systematic, computer-based design of linker groups such as that discussed by Walker et al (1995), one must know the precise positioning of drug monomers on the DNA duplex. Even a slight mispositioning of drug will lead to erroneous geometry for the linkers to be synthesized.…”

Section: Dykementioning

confidence: 99%

“…Because the precise alignment of the netropsin molecule on DNA is so critical to systematic drug design, especially the synthesis of bis-linked dimers (Walker et al, 1995), we have reexamined the issue of class I vs class II positioning of the netropsin molecule in its DNA complex. Using the original netropsin/CGCGAATT5BrCGCG data, we have rerefined netropsin both in the class I position presented by Kopka et al (1985a-c) and in the class II alternative reported more recently by Sriram et al (1992).…”

Section: Dykementioning

confidence: 99%

Refinement of Netropsin Bound to DNA: Bias and Feedback in Electron Density Map Interpretation

Goodsell¹,

1995

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The X-ray crystal structure of the complex of the B-DNA dodecamer CGCGAATTCGCG with the antitumor drug netropsin has been reexamined to locate the drug accurately for computer-based drug design. The optimum solution is with the drug centered in the AATT region of the minor groove, making three good bifurcated hydrogen bonds with adenine N3 and thymine O2 atoms along the floor of the groove. Pyrrole rings of netropsin are packed against the C2 positions of adenines, leaving no room for the amine group of guanine and, hence, providing a structural rationale for the A.T specificity of netropsin. An alternative positioning in which the drug is shifted along the minor groove by ca. one-half base pair step is rejected on the basis of free R factor calculations and the appearance of the original drug-free difference maps. Final omit maps, although of more pleasing appearance, are not a dependable means of discriminating between right and wrong structures. The shifted alternative drug position ignores potential hydrogen bonding along the floor of the groove, provides no explanation for netropsin's observed A.T specificity, and is contradicted by NMR results [Patel, D. J. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 6424].

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“…The first DNA-interactive anticancer drugs belong to the family of the covalently binding DNA alkylating agents (6,7). In recent years, ligands that bind non-covalently in the minor groove have attracted considerable attention because of their pronounced sequence specificity (8).…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulations and free energy calculations of netropsin and distamycin binding to an AAAAA DNA binding site

Dolenc

Oostenbrink²,

Koller³

et al. 2005

Nucleic Acids Research

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Molecular dynamics simulations have been performed on netropsin in two different charge states and on distamycin binding to the minor groove of the DNA duplex d(CGCGAAAAACGCG)·d(CGCGTTTTTCGCG). The relative free energy of binding of the two non-covalently interacting ligands was calculated using the thermodynamic integration method and reflects the experimental result. From 2 ns simulations of the ligands free in solution and when bound to DNA, the mobility and the hydrogen-bonding patterns of the ligands were studied, as well as their hydration. It is shown that even though distamycin is less hydrated than netropsin, the loss of ligand–solvent interactions is very similar for both ligands. The relative mobilities of the ligands in their bound and free forms indicate a larger entropic penalty for distamycin when binding to the minor groove compared with netropsin, partially explaining the lower binding affinity of the distamycin molecule. The detailed structural and energetic insights obtained from the molecular dynamics simulations allow for a better understanding of the factors determining ligand–DNA binding.

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Design of B‐DNA cross‐linking and sequence‐reading molecules

Cited by 19 publications

References 28 publications

DNA Cross-Linking Agents as Antitumor Drugs

DNA Cross-Linking Agents as Antitumor Drugs

Refinement of Netropsin Bound to DNA: Bias and Feedback in Electron Density Map Interpretation

Molecular dynamics simulations and free energy calculations of netropsin and distamycin binding to an AAAAA DNA binding site

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