Molecular recognition of DNA by small molecules: AT base pair specific intercalative binding of cytotoxic plant alkaloid palmatine (original) (raw)
Related papers
Journal of Molecular Structure, 2008
The interaction of two natural protoberberine plant alkaloids berberine and palmatine with tRNAphe was studied using various biophysical techniques and molecular modeling and the data were compared with the binding of the classical DNA intercalator, ethidium. Circular dichroic studies revealed that the tRNA conformation was moderately perturbed on binding of the alkaloids. The cooperative binding of both the alkaloids and ethidium to tRNA was revealed from absorbance and fluorescence studies. Fluorescence quenching studies advanced a conclusion that while berberine and palmatine are partially intercalated, ethidium is fully intercalated on the tRNA molecule. The binding of the alkaloids as well as ethidium stabilized the tRNA melting, and the binding constant evaluated from the averaged optical melting temperature data was in agreement with fluorescence spectral-binding data. Differential scanning calorimetry revealed that the tRNA melting showed three close transitions that were affected on binding of these small molecules. Molecular docking calculations performed showed the preferred regions of binding of these small molecules on the tRNA. Taken together, the results suggest that the binding of the alkaloids berberine and palmatine on the tRNA structure appears to be mostly by partial intercalation while ethidium intercalates fully on the tRNA. These results further advance our knowledge on the molecular aspects on the interaction of these alkaloids to tRNA.
Nucleic Acids Research, 1982
The interaction with closed circular supercoiled and linear DNA of bisphenanthridinium compounds substituted through both the meta and para positions of the 6-phenyl group, along with appropriate monomer intercalators as controls, has been investigated by viscometric titration. When CPK models for the phenanthridinium rings of the three bis-compounds are oriented in a parallel manner as a model for intercalation, their ring plane to ring plane distances are approximately 7 to 8 A (SR 2430), 11 A (SR 2193), and 15 A (SR 2166). In SR 2430 the two phenanthridines are linked through the para positions of the 6-phenyl group; this chain allows intercalation of the two rings at adjacent binding sites in DNA, but is not long enough to acconmnodate an excluded site between bound rings. The other two compounds, SR 2193 and 2166, joined through the meta positions of the 6-phenyl, can double intercalate with an excluded site. The viscometric titrations with both superhelical and linear DNA clearly indicate that SR 2430 gives results close to those of the monomer control compounds while SR 2193 and SR 2166 have approximately twice the unwinding angle and DNA length increase on binding to DNA as the monomer compounds. These phenanthridinium compounds, therefore, are capable of bisintercalation only if their linking groups are of sufficient length to allow an excluded binding site between base pairs. This conclusion is supported by DNA thermal denaturation experiments in the presence of these compounds.
Binding of alkaloid harmalol to DNA: Photophysical and calorimetric approach
Journal of Photochemistry and Photobiology B: Biology, 2014
Harmalol exhibits pH dependent structural equilibrium between protonated and deprotonated forms with a pK a of 7.8 as revealed from spectroscopic titration. The compound exists as protonated (structure I) and deprotonated (structure II) form in the pH range 1-7 and 9-12, respectively. The interaction of structure I and II to calf thymus DNA has been studied by different spectroscopic and calorimetric techniques in buffer of pH 6.8 and 9.2, respectively. The results show that structure I bind strongly to DNA showing a cooperative mode with a binding constant of 4.5 Â 10 5 M À1 and a stoichiometry of 4.8 nucleotide phosphates. The alkaloid stabilized the DNA by 8°C, the binding shows 40% quenching of fluorescence intensity, perturbation in circular dichroism spectra and enthalpy driven exothermic binding with a large hydrophobic contribution to the binding free energy. Furthermore, the alkaloid shows a prominent change of specific viscosity with sonicated linear DNA and unwinding-rewinding of covalently closed pUC 18 DNA, revealing intercalative binding. The deprotonated structure (structure II), on the other hand, in the presence of large amount of DNA concentration, converts back to a structure I-DNA complexation. This transition has been presumably induced by the polyanionic phosphate backbone of DNA at high concentration.
Journal of Pharmaceutical Sciences, 1978
- along with the restrictions on M of M (O) = 0 and M ' (0) = 0. Within these limitations, Eq. 1 3 is a rather general relationship between the disintegration and dissolution of a tablet. Any function M that fits the t.ahlet, dissolution dat.a and meets these restrictions may be substituted into Eq. I:{ to give an explicit expression for the disintegration. Another ramification of Eq. 13 is that it would be possible to determine the disintegration profile in real bime if k is known by using the output signal from the spectrophotometer or potentiometer that is monitoring the tablet dissolnt~ion as input for an analog computer programmed for Eq. 13. The dissolution and disintegration profiles could thereby he det ermined si rn u1t aneously.
J Mol Biol, 2002
Phenylamidine cationic groups linked by a furan ring (furamidine) and related symmetric diamidine compounds bind as monomers in the minor groove of AT sequences of DNA. DB293, an unsymmetric derivative with one of the phenyl rings of furamidine replaced with a benzimidazole, can bind to AT sequences as a monomer but binds more strongly to GC-containing minor-groove DNA sites as a stacked dimer. The dimer-binding mode has high af®nity, is highly cooperative and sequence selective. In order to develop a better understanding of the correlation between structural and thermodynamic aspects of DNA molecular recognition, DB293 was used as a model to compare the binding of minor-groove agents with AT and mixed sequence DNA sites. Isothermal titration calorimetry and surface plasmon resonance results clearly show that the binding of DB293 and other related compounds into the minor groove of AT sequences is largely entropy-driven while the binding of DB293 as a dimer into the minor groove of GC-containing sequences is largely enthalpy-driven. At 25 C, for example, the AT binding has ÁG , ÁH and TÁS values of À9.6, À3.6 and 6.0 kcal/mol while the values for dimer binding to a GC-containing site are À9.0, À10.9 and À1.9 kcal/mol (per mol of bound compound), respectively. These results show that the thermodynamic components for binding of compounds of this type to DNA are very dependent on the structure, solvation and sequence of the DNA binding site.
Journal of Molecular Biology, 2002
Phenylamidine cationic groups linked by a furan ring (furamidine) and related symmetric diamidine compounds bind as monomers in the minor groove of AT sequences of DNA. DB293, an unsymmetric derivative with one of the phenyl rings of furamidine replaced with a benzimidazole, can bind to AT sequences as a monomer but binds more strongly to GC-containing minor-groove DNA sites as a stacked dimer. The dimer-binding mode has high af®nity, is highly cooperative and sequence selective. In order to develop a better understanding of the correlation between structural and thermodynamic aspects of DNA molecular recognition, DB293 was used as a model to compare the binding of minor-groove agents with AT and mixed sequence DNA sites. Isothermal titration calorimetry and surface plasmon resonance results clearly show that the binding of DB293 and other related compounds into the minor groove of AT sequences is largely entropy-driven while the binding of DB293 as a dimer into the minor groove of GC-containing sequences is largely enthalpy-driven. At 25 C, for example, the AT binding has ÁG , ÁH and TÁS values of À9.6, À3.6 and 6.0 kcal/mol while the values for dimer binding to a GC-containing site are À9.0, À10.9 and À1.9 kcal/mol (per mol of bound compound), respectively. These results show that the thermodynamic components for binding of compounds of this type to DNA are very dependent on the structure, solvation and sequence of the DNA binding site.
DNA polyintercalating drugs: DNA binding of diacridine derivatives
Proceedings of the National Academy of Sciences, 1975
As a first step in the synthesis and the study of DNA polyintercalating drugs, dimers of acridines have been prepared. Their DNA binding properties have been studied. It has been determined that wen the chain separating the two aromatic rings is longer than a critical distance, bisintercalation is actually observed and that the DNA binding affinity becomes quite large (>108-109 M-1). It is shown also that the optical characteristics of these molecules are dependent on the sequences of DNA. The fluorescence intensity of one of these dimers when bound to DNA varies as the fourth power of its A+T content. This derivative could be used as a fluorescent probe of DNA sequence.
Drug-DNA sequence-dependent interactions analysed by electric linear dichroism
Journal of Molecular Recognition, 1992
The interactions between 20 drugs and a variety of synthetic DNA polymers and natural DNAs were studied by electric linear dichroism (ELD). All compounds tested, including several clinically used antitumour agents, are thought to exert their biological activities mainly by virtue of their abilities to bind to DNA. The selected drugs include intercalating agents with fused and unfused aromatic structures and several groove binders. To examine the role of base composition and base sequence in the binding of these drugs to DNA, ELD experiments were carried out with natural DNAs of widely differing base composition as well as with polynucleotides containing defined alternating and non-alternating repeating sequences, poly(dA).poly(dT),poly(dA-dT).poly(dA-dT),poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC). Among intercalating agents, actinomycin D was found to be by far the most GC-selective. GC selectivity was also observed with an amsacrine-4-carboxamide derivative and to a lesser extent with methylene blue. In contrast, the binding of amsacrine and 9-aminoacridine was practically unaffected by varying the GC content of the DNAs. Ethidium bromide, proflavine, mitoxantrone, daunomycin and an ellipticine derivative were found to bind best to alternating purine-pyrimidine sequences regardless of their nature. ELD measurements provided evidence for non-specific intercalation of amiloride. A significant AT selectivity was observed with hycanthone and lucanthone. The triphenyl methane dye methyl green was found to exhibit positive and negative dichroism signals at AT and GC sites, respectively, showing that the mode of binding of a drug can change markedly with the DNA base composition. Among minor groove binders, the N-methylpyrrole carboxamide-containing antibiotics netropsin and distamycin bound to DNA with very pronounced AT specificity, as expected. More interestingly the dye Hoechst 33258, berenil and a thiazolecontaining lexitropsin elicited negative reduced dichroism in the presence of GC-rich DNA which is totally inconsistent with a groove binding process. We postulate that these three drugs share with the trypanocide 4',6diamidino-2-phenylindole (DAPI) the property of intercalating at GC-rich sites and binding to the minor groove of DNA at other sites. Replacement of guanines by inosines (i.e., removal of the protruding exocyclic C-2 amino group of guanine) restored minor groove binding of DAPI, Hoechst 33258 and berenil. Thus there are several cases where the mode of binding to DNA is directly dependent on the base composition of the polymer. Consequently the ELD technique appears uniquely valuable as a means of investigating the possibility of sequence-dependent recognition of DNA by drugs.
A Study on binding of hydroxamic acid derivative to DNA: experimental and computational approach
2016
Small ligand molecules bind to DNA and artificially alter and/or inhibit the functioning of DNA. These small ligand molecules act as drug when alteration or inhibition of DNA function is required to cure or control a disease.The binding interaction of N-phenyllauroylhydroxamic acid with CTDNA was measured by four methods, (i) UV spectroscopic method, (ii) fluorescence spectroscopic method, (iii) viscosity Measurement and (iv) molecular docking. It showed that Nphenyllauroylhydroxamic acid-DNA complex has high absorption intensity than compound only and significant quenching of fluorescence intensity for the N-phenyllauroylhydroxamic-DNA complex. The values of binding constant, K, is 3.43x 10and Stern Volmer constant Ksv is 4.8x10 2 ngμl obtained by UV absorption and fluorescence spectral methods, respectively. The binding interaction is further confirmed by the increase in relative viscosity of CT-DNA. The molecular docking of N-phenyllauroylhydroxamic acid with the DNA confirmed to...
Deciphering the binding mode of dinitramine herbicide to ct-DNA, a thermodynamic discussion
Food and Agricultural Immunology, 2015
Dinitramine is a herbicide that has been used to control annual grasses and broadleaf weeds in cotton and soybeans in Iran. In this study, the electrochemical behavior of dinitramine was studied by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) methods. The interaction of dinitramine with ct-DNA was evaluated by CV, competitive fluorescence, UV-Vis spectroscopy, FT-IR spectroscopy, and viscosity titration. In addition, the thermodynamic parameters of DIN-DNA complex were calculated by spectrophotometric titration. The values of ΔH bin. , ΔS bin., and ΔG bin. (T = 290.65 K) of the DIN-DNA complex were +39.25 kJ mol −1 , +215.71 J mol −1, and −23.45 KJ mol −1 , respectively. These data revealed that the endothermic binding has its origin in the hydrophobic interactions. Also the high positive ΔS bin was explained according to the DIN structure that optimized by mechanical quantum calculations. However, all data showed that the major groove binding between DIN and ct-DNA is more predominant than other binding modes.