Binding of Analogues of the Antibiotics Distamycin A and Netropsin to Native DNA

Zimmeer, Christoph; Luck, G.; Thrum, H.; Pitra, Christian

doi:10.1111/j.1432-1033.1972.tb01742.x

Cited by 63 publications

(27 citation statements)

References 16 publications

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“…Similar results have been obtained from footprinting ( 10,1 2), calorimetric ( 13), X -ray (14)(15)(16)(17) and NMR (18)(19)(20)(21)(22) studies of netropsin-DNA complexes, and also Hoechst 33258-DNA complexes (23)(24)(25). Together, the data on distamycin A, netropsin, and Hoechst 33258, as well as that obtained from other minor groove binding antibiotics (26)(27)(28) indicate that hydrogen bonds, electrostatic forces (29), and both van der Waals and hydrophobic (30) interactions are important in stabilizing these complexes and in determining the sequence specificity of these drugs.…”

Section: Introductionmentioning

confidence: 76%

Structure and Dynamics of Distamycin A with d(CGCAAATTGGC):d(GCCAATTTGCG) at Low Drug: DNA Ratios

Wemmer

1990

Journal of Biomolecular Structure and Dynamics

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Two-dimensional NMR has been used to study the interaction of distamycin A with d(CGCAAATTGGC):d(GCCAATTTGCG) at low and intermediate drug:DNA ratios (less than 2.0). Drug-DNA contacts were identified by nuclear Overhauser effect spectroscopy, which also served to monitor exchange of the drug between different binding sites. At low drug:DNA ratios (0.5), distamycin A binds in two orientations within the five central A-T base pairs and has a preference (2.2:1) for binding with the formyl end directed toward the 5' side of the A-rich strand. The pattern of drug-DNA contacts corresponding to the preferred binding orientation are consistent with the drug sliding between adjacent AAAT and AATT binding sites at a rate that is fast on the NMR time scale. Similarly, the pattern of NOEs associated with the less favored orientation are consistent with the drug sliding between adjacent AATT and ATTT sites, again in fast exchange. Off-rates for the drug from the major and minor binding orientations were measured to be 2.4 +/- 1.5 and 3.3 +/- 1.5 s-1, respectively, at 35 degrees C. At intermediate drug:DNA ratios (1.3) exchange of the drug between the two one-drug and the two sites of a two-drug complex is observed. Off-rates for both drugs from the 2:1 complex were measured to be 1.0 +/- 0.5 s-1 (35 degrees C).

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Section: Introductionmentioning

confidence: 76%

Structure and Dynamics of Distamycin A with d(CGCAAATTGGC):d(GCCAATTTGCG) at Low Drug: DNA Ratios

Wemmer

1990

Journal of Biomolecular Structure and Dynamics

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“…In class I structures, the amide groups form bifurcated hydrogen bonds to N3(A) and O2(T) atoms on opposite strands, thereby displacing the spine of hydration and providing an understanding for the molecular origin of its AT specificity in agreement with results obtained from NMR studies. Modified NTR molecules with the amidinium and guanidinium ends removed, as well as NTR analogues with cationic ends but with no H-bonding capabilities, exhibit both an appreciable binding to DNA and a preference for AT base pairs [34,35]. Electrostatic interactions between the negatively charged minor groove and the positively charged end groups of the drug are an important factor in complex formation.…”

Section: Ab Initio Quantum Chemical Methodsmentioning

confidence: 99%

DNA Minor Groove Binders: an Overview on Molecular Modeling and QSAR Approaches

Lauria

Montalbano²,

Barraja³

et al. 2007

CMC

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Molecular recognition of DNA by small molecules and proteins is a fundamental problem in structural biology and drug design. Understanding of recognition in both sequence-selective and sequence neutral ways at the level of successful prediction of binding modes and site selectivity will be instrumental for improvements in the design and synthesis of new molecules as potent and selective gene-regulatory drugs. Minor groove is the target of a large number of non-covalent binding agents. DNA binding with specific sequences, mostly AT, takes place by means of a combination of directed hydrogen bonding to base pair edges, van der Waals interactions with the minor groove walls and generalized electrostatic interactions. These factors are also responsible for protein-DNA recognition, and a number of unifying rules governing the interactions have been elucidated although it has been realized that the earlier goal of a simple recognition code between amino acids and bases is not attainable. At present relatively little is understood about the mode of action at the molecular level of the majority of minor groove-interacting drugs, although there is increasing evidence that they may act by directly blocking or inhibiting protein-DNA recognition. The present review has the aim to focus on interactions between minor groove binders and DNA through a variety of techniques that are commonly used to analyze the DNA binding properties of small molecules. In fact in the last years several articles dealing with in silico techniques on DNA minor groove binders (molecular modeling, molecular dynamics, QSAR) have been published. All these studies can be considered a support in defining valid predictive models. For this reason a compendium of all matter could be an useful support for future developments.

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“…ly essential, since netropsin modifications with the cationic ends removed, and analogues with cationic ends but without hydrogen bonding capabilities, show both an appreciable binding to B-DNA and base specificity for A-T base pairs (4,14,15).…”

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confidence: 99%

The molecular origin of DNA-drug specificity in netropsin and distamycin.

Kopka¹,

Yoon²,

Goodsell³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

800

577

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X-ray analysis of the complex of netropsin with the B-DNA dodecamer of sequence C-G-C-G-A-A-T-TBrC-G-C-G reveals that the antitumor antibiotic binds within the minor groove by displacing the water molecules of the spine of hydration. Netropsin amide NH furnish hydrogen bonds to bridge DNA adenine N-3 and thymine 0-2 atoms occurring on adjacent base pairs and opposite helix strands, exactly as with the spine of hydration. The narrowness of the groove forces the netropsin molecule to sit symmetrically in the center, with its two pyrrole rings slightly non-coplanar so that each ring is parallel to the walls of its respective region of the groove. Drug binding neither unwinds nor elongates the double helix, but it does force open the minor groove by 0.5-2.0 A, and it bends back the helix axis by 8°across the region of attachment. The netropsin molecule has an intrinsic twist that favors insertion into the minor groove of B-DNA, and it is given a small additional twist upon binding. The base specificity that makes netropsin bind preferentially to runs of four or more ACT base pairs is provided not by hydrogen bonding but by close van der Waals contacts between adenine C-2 hydrogens and CH groups on the pyrrole rings of the drug molecule. Substitution of one or more pyrroles by imidazole could permit recognition of G'C base pairs as well, and it could lead to a class of synthetic "lexitropsins," capable of reading any desired short sequence of DNA base pairs.Netropsin and its close relative distamycin ( Fig. 1) are antiviral antitumor antibiotics that, although too toxic for clinical use, have received extensive study as the paradigms of base-specific yet non-intercalative DNA-binding drug molecules. First isolated from Streptomyces netropsis in 1951 (1, 2), netropsin exerts its biological activity by binding tightly to double-helical B-DNA, interfering with both replication and transcription (3, 4). It shows little or no affinity for single-stranded DNA or RNA or for double-stranded RNA or DNA-RNA hybrids (3-5), suggesting that it does not bind to the A helix. It also fails to bind to left-handed Z-DNA; in fact, binding of netropsin to DNA favors A-to-B and Z-to-B helix transitions (6, 7).Chemical protection studies (3,4,8) and Overhauser NMR experiments (9) indicate that netropsin does not intercalate between base pairs, but it binds within the minor groove of the intact double helix, using hydrogen bonds between netropsin amide NH and exposed adenine N-3 and thymine 0-2 on the floor of the minor groove. The drug molecule attaches to clusters of four or more A'T or ITC, but not to G-C, base pairs (3, 10, 11). Alternating A-T-A-T regions bind netropsin less well than continuous runs of A or T (12, 13). Binding involves both an electrostatic component from the two cationic ends and hydrogen bonds from the central three amide NH groups, although neither aspect is absolute- FIG. 1. The netropsin molecule can be regarded as being assembled from (left to right): guanidinium, amide, methylpyrrole, amide, methylpyrr...

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Binding of Analogues of the Antibiotics Distamycin A and Netropsin to Native DNA

Cited by 63 publications

References 16 publications

Structure and Dynamics of Distamycin A with d(CGCAAATTGGC):d(GCCAATTTGCG) at Low Drug: DNA Ratios

Structure and Dynamics of Distamycin A with d(CGCAAATTGGC):d(GCCAATTTGCG) at Low Drug: DNA Ratios

DNA Minor Groove Binders: an Overview on Molecular Modeling and QSAR Approaches

The molecular origin of DNA-drug specificity in netropsin and distamycin.

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