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PubMedDate not supplied

ADAPT: a molecular mechanics approach for studying the structural properties of long DNA sequences.

We describe an original approach to determining sequence-structure relationships for DNA. This approach, termed ADAPT, combines all-atom molecular mechanics with a multicopy algorithm to build nucleotides that contain all four standard bases in variable proportions. These nucleotides enable us to search very rapidly for base sequences that energetically favor chosen types of DNA deformation or chosen DNA-protein or DNA-ligand interactions. Sequences satisfying the chosen criteria can be found by energy minimization, combinatorial sequence searching, or genome scanning, in a manner similar to the threading approaches developed for protein structure prediction. In the latter case, we are able to analyze roughly 2000 base pairs per second. Applications of the method to DNA allomorphic transitions, DNA deformation, and specific DNA interactions are presented.

Algorithms↗
PubMed1992

Differential hydration of homopurine sequences relative to alternating purine/pyrimidine sequences.

The minor groove ligand distamycin A has been used to probe the relative hydration of the minor groove of eight synthetic polynucleotides of known sequence and composition. A combination of densimetric, calorimetric, and temperature-dependent spectroscopic techniques have been used to obtain complete thermodynamic profiles (delta Gzero, delta Hzero, delta Szero, and delta Vzero) for the association of distamycin A to all polymer duplexes. In 10 mM phosphate buffer, pH 7, binding of the drug to each of the polymeric duplexes resulted in characteristic negative changes in both the volume and enthalpy. Although the binding constants were found to be identical for pairs of isomer polynucleotides having identical compositions but different sequences, the values of delta Hzero, delta Szero, and delta Vzero of each such pair were remarkably different. The entropy changes were found to roughly parallel the volume changes; no such trend was seen between delta Hzero and delta Vzero. The data support the hypothesis that the volume changes observed for these systems reflect the coulombic-hydration contribution to the entropy. The heteropolymer duplexes generated much larger exothermic contributions, less favorable entropies and larger volume contractions than did the corresponding homopolymer duplexes of identical composition, and strongly suggest that polynucleotides with homopurine sequences are more hydrated than polynucleotides with alternating purine/pyrimidine sequences. In addition, it was found that duplexes containing guanine sharply reduced the affinity for the drug, also lowering the exothermicity but raising the entropy. This may be explained by the presence of an amino group in the minor groove that prevents hydrogen bonding. Substitution of the guanine with inosine reversed this trend in the thermodynamic properties. Furthermore, substitution of poly(dA) for poly(rA) in a duplex produced a similar reduction in the affinity, while raising the exothermic contribution and greatly reducing the favorable entropy effect in agreement with an apparent increase in the hydration state.

Base Sequence↗
PubMed2004

The biological effects of N3-methyladenine.

The targeting of damage to DNA remains an attractive strategy to kill tumor cells. One of the serious side effects of alkylating agents is that they create both toxic (desired) and mutagenic (undesired) lesions. The result is that patients successfully treated for a primary cancer are at significant risk to develop cancer related to their therapy. To address this issue we have prepared agents that selectively methylate DNA at the N3-position of adenine. The presence of this lesion in DNA is thought to halt DNA polymerase, and this then initiates a cascade of events including cell death. The toxicity and mutagenicity of the compound, Me-lex, used to generate N3-methyladenine is discussed in bacterial, yeast, and mammalian systems. Mechanisms are proposed to explain the biological activities of N3-methyladenine.

Adenine↗
PubMed1994

DNA recognition by lexitropsins, minor groove binding agents.

Consideration is given to alternative approaches to the development of DNA sequence selective binding agents because of their potential applications in diagnosis and treatment of cancer as well as in molecular biology. The concept of lexitropsins, or information-reading molecules, is introduced within the antigene strategy as an alternative to, and complementary with, the antisense approach for cellular intervention and gene control. The chemical, physical and pharmacological factors involved in the design of effective lexitropsins are discussed and illustrated with experimental results. Among the factors contributing to the molecular recognition processes are: the presence and disposition of hydrogen bond accepting and donating groups, ligand shape, chirality, stereochemistry, flexibility and charge. For longer ligands, such as are required to target unique sequences in biological systems (14-16 base pairs), the critical feature is the phasing or spatial correspondence between repeat units in the ligand and the receptor. The recently discovered 2:1 lexitropsin-DNA binding motif provides a further refinement in molecular recognition in permitting discrimination between GC and CG base pairs. The application of these factors in the design and synthesis of novel agents which exhibit anticancer, antiviral and antiretroviral properties, and inhibition of critical cellular enzymes including topoisomerases is discussed. The emerging evidence of a relationship between sequence selectivity of the new agents and the biological responses they invoked is also described.

Animals↗
PubMed1980

Structure-activity relationships of pyrrole amidine antiviral antibiotics III: preparation of distamycin and congocidine derivatives based on 2,5-disubstituted pyrroles.

Isomers of distamycin A and tripyrrole congocidine containing 2,5-disubstituted pyrroles were synthesized along with distamycin and congocidine homologs containing a single pyrrole ring. Selected compounds were evaluated for their cytotoxicity and antiviral activity. All of the tripyrrole derivatives tested in this series were nontoxic but were less active than distamycin A. The monopyrrole derivative, N-methyl-5-nitropyrrole-2-carboxamido-beta-propionamidine hydrochloride, was nontoxic and was almost as active antivirally as distamycin A.

Antiviral Agents↗
PubMed1981

Antiparasitic structure-activity relationships of congocidine derivatives.

Several congocidine analogs were synthesized and tested for in vivo activity against Trypanosoma congolense and in vitro activity against amastigotes of Leishmania tropica. The tripyrrole derivative, beta-([N-methyl-4-[N-methyl-4-(guanidinoacetamido)pyrrole-2-carboxamido]pyrrole -2-carboxamido]pyrrole-2-carboxamido)butyroamidine dihydrochloride, was less toxic and more active than congocidine. The guanidinoacetyl moiety appears to be a structural requirement for antiparasitic activity in the congocidine series.

Animals↗
PubMed2001

Electrospray tandem mass spectrometry of lexitropsins.

Several compounds, representative of the class of lexitropsins, were analyzed by electrospray tandem mass spectrometry. The study of the fragmentations of the protonated molecular species ([M + H](+)) and of selected fragment ions allowed proposals for the main fragmentation pathways of compounds of this type. The interpretation of the fragmentation pathways of these compounds was complicated because of intramolecular hydrogen migration. In order to better understand the fragmentation pathways, the MS/MS/MS spectra of several compounds, and the MS/MS and MS/MS/MS spectra of the deuterated compounds, were obtained. Accurate mass measurements helped elucidate the structures of smaller fragment ions. Low-energy collision-induced decomposition (CID) tandem mass spectrometry of lexitropsins with electrospray ionization has proven to be a good method for the structural characterization and identification of this class of compounds. Main fragmentation pathways occur by cleavage of the peptide bond followed by the elimination of the substituted pyrrole ring, and their elucidation will facilitate structural characterization of new lexitropsins.

Antineoplastic Agents↗
PubMed1993

Effect of topoisomerase inhibitors on the in vitro HIV DNA integration reaction.

Retroviral growth requires as an obligatory step the integration of a DNA copy of the viral RNA into the genomic DNA of the host. Recombinant human immunodeficiency virus type I (HIV-1) integrase (IN) expressed in Escherichia coli efficiently catalyzes the overall in vitro integration reaction, namely, the processing of the LTR ends and the strand transfer reaction. Using the 3' end of synthetic oligonucleotides which match the termini of the HIV-I U5 LTR as substrate and supercoiled pSP65 DNA as target, we have measured the effect of various topoisomerase inhibitors on the functional activity of the IN protein. Among the various drugs tested, the antitumor drug 2N-Methyl, 9-hydroxyellipticinium (NMHE) displays a marked inhibitory effect on the IN-catalyzed U5 insertion. This effect is related to the DNA binding properties of the drug rather than to a selective effect on the IN protein or the DNA-IN protein complex.

Amsacrine↗
PubMed1994

Sugar-DNA molecular recognition: specific interaction of alpha-1,4-glucopyranose chains with DNA in the minor groove.

alpha(1,4) glucopyranose chains (dextrins) are shown to interact with DNA via hydrophobic interactions from the minor groove side, while alpha(1,6) dextrans do not bind DNA. The observed specific alpha(1,4) linked sugar-DNA interactions may have importance in recognition of DNA by ene-diyne class of antibiotics via their saccharide units which have mostly alpha(1,4) linkages.

Base Sequence↗
PubMed1998

Water molecules in DNA recognition I: hydration lifetimes of trp operator DNA in solution measured by NMR spectroscopy.

The present NMR study investigates the residence times of the hydration water molecules associated with uncomplexed trp operator DNA in solution by measuring intermolecular nuclear Overhauser effects (NOE) between water and DNA protons, and the nuclear magnetic relaxation dispersion (NMRD) of the water 2H and 17O resonances. Both methods indicate that the hydration water molecules exchange with bulk water on the sub-nanosecond time scale at 4 degreesC. No evidence was obtained for water molecules bound with longer residence times. In particular, the water molecules at the sites of interfacial hydration in the trp repressor/operator complex do not seem kinetically stabilized in the uncomplexed DNA. Analysis of the crystal structures of two different trp repressor/operator complexes shows very similar structural environments for the water molecules mediating specific contacts between the protein and the DNA, whereas much larger variations are observed for the location of corresponding water molecules detected in the crystal structure of an uncomplexed trp operator DNA duplex. Therefore, it appears unlikely that the hydration characteristics of the uncomplexed DNA target would be a major determinant of trp repressor/operator recognition.

Bacterial Proteins↗
PubMed1995

New molecular shape descriptors: application in database screening.

Geometric descriptors are becoming popular tools for encoding molecular shape, for use in database screening and clustering calculations. They provide condensed representations of complex objects and, as a consequence, can usually be compared quite rapidly. Here we present a number of new descriptors and methods for the quantification of molecular shape similarity. The techniques are tested using two different biological systems, with particular emphasis on their potential utility as methods for prescreening shape-based database searches. Results are compared with data sets produced using the DOCK program. We find that such similarity evaluations are useful for finding molecules with complementary shape, and that they contain an enriched number of potential DOCK hits when compared to the original databases. Significant limitations in the utility of such DOCK prescreens are discussed, and potential solutions are considered.

Binding Sites↗
PubMed2002

Apoptotic and genotoxic effects of a methyl sulfonate ester that selectively generates N3-methyladenine and poly(ADP-ribose) polymerase inhibitors in normal peripheral blood lymphocytes.

UNLABELLED: Selective N3-adenine methylation represents a novel strategy for tumors with a phenotype of poor responsiveness to a number of anticancer agents currently used in the clinic. Resistance to N3-methyladenine-inducing agents, such as MeOSO(2)(CH(2))(2)-lexitropsin (Me-Lex), is due to high levels of N-methylpurine glycosylase (MPG). However, tumor cells with high MPG activity can be rendered susceptible to Me-Lex using poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. PURPOSE: To evaluate the potential toxicity of Me-Lex, used as single agent or combined with PARP-1 inhibitors, in normal peripheral blood lymphocytes (PBL). METHODS: PBL either resting or activated with phytohemagglutinin (PHA), obtained from healthy donors, were treated with graded concentrations of Me-Lex with or without PARP-1 inhibitor (3-aminobenzamide, AB, or NU1025, NU). MPG activity, apoptosis and sister chromatid exchanges (SCE) were evaluated. RESULTS: (a) Me-Lex was cytotoxic mainly in PHA-activated PBL with low MPG activity; (b) combined treatment with Me-Lex and AB induced apoptotic effects as early as 24 h after drug exposure both in non-stimulated and PHA-activated PBL. When concentrations of PARP-1 inhibitors (25 microM NU and 4 m M AB) that produced a twofold increase in Me-Lex cytotoxicity in tumor cells were compared, NU induced a less-pronounced increase in apoptosis in PBL treated with Me-Lex; (c) Me-Lex at concentrations that allowed cytogenetic analysis did not induce a significant number of SCE; (d) PARP-1 inhibitors provoked a dose-dependent increase in SCE, but 25 microM NU was devoid of genotoxic effects and did not significantly increase SCE in PBL treated with Me-Lex. CONCLUSIONS: Me-Lex showed preferential cytotoxicity against mitogen-activated PBL. Our results also indicated that for each PARP-1 inhibitor it is necessary to define the concentration devoid of genotoxic effects in normal cells, but still capable of enhancing the efficacy of DNA-damaging agents in tumor cells.

Alkylating Agents↗
PubMed1989

Footprinting analysis of sequence-specific DNA-drug interactions.

Footprinting is a technique widely used in the analysis of sequence-specificity of proteins and drugs which bind to DNA in an equilibrium manner. Footprinting studies combine the enzymatic or chemical cleavage of DNA with the analysis of the resulting products by sequencing gels, thus revealing the position and length of individual binding sites. This review compares the information that can be obtained by using different footprinting agents and the characteristics of DNA-drug interactions that can be inferred from footprinting results.

Base Sequence↗
PubMed1989

A model for the ability of drugs to induce enhanced DNase I cleavage.

A common property of sequence-selective DNA-binding drugs lies in their ability to induce an enhanced DNase I cleavage in regions surrounding their binding sites. A hypothetical model to explain the enhancements induced by drug binding to the minor-groove of DNA is presented. It involves the participation of three different single models: a mass action effect produced by the enzyme redistribution after drug binding; changes in the minor groove width size; and interactions between the enzyme and the drug, so increasing the cleavage in places located close to the binding site. The model is tested by using statistical data analysis. The hypothetical model might explain the experimental results better than any of the single models alone, but these models also appear to render significant results.

Base Sequence↗
PubMed1993

Minor-groove binders are inhibitors of the catalytic activity of DNA gyrases.

Non-intercalating DNA minor-groove binders may effectively inhibit the supercoiling activity of gyrases by influencing the enzyme recognition and cleavage site on DNA. For gyrase from Streptomyces noursei a wide range of inhibitory potency for different classes of ligands is observed. This can be explained by a number of structural and binding factors of the ligands competing with the gyrase on the target site of DNA, the mechanism of which is different from the classical gyrase inhibitors.

Animals↗