Benzothiadiazoles as DNA intercalators: Docking and simulation

Abstract

Some organic dyes, derivatives of the 4-(arylethynyl)-7-(4-methoxyphenyl)-2,1,3-benzothiadiazoles (BTDs) bind strongly to double stranded DNA, exhibiting a strong increase in the fluorescence intensity. Due to this property, they were proposed as very sensitive probes for DNA detection and quantification.The details of the interaction mechanism, however, are unknown. In this work, we use docking and molecular dynamics simulations to study the interactions of these BTDs with DNA. We used a docking protocol where the receptor is a modified canonical oligonucleotide, with a gap, to sample intercalation and minor groove binding modes. Starting from several independent but energetically favorable docking poses, molecular dynamics simulations were carried out, investigating the ligand-DNA interactions and the time evolution of the DNA structure. We observed, in agreement with experimental results, that the presence of the ethynyl spacer in the ligand stabilizes the intercalation binding mode, yielding strong interactions with DNA and large residence times.

Bis-triazolylchalcogenium-Functionalized Benzothiadiazole Derivatives as Light-up Sensors for DNA and BSA

“…Compounds 3c and 3g presented higher affinity with DNA compared to the BSA target. Nonetheless, compounds 3a , 3b , 3d , 3e , and 3f have more affinity with the albumin biomolecule despite still having a considerably high affinity with DNA …”

“…Nonetheless, compounds 3a, 3b, 3d, 3e, and 3f have more affinity with the albumin biomolecule despite still having a considerably high affinity with DNA. 30 It is widely known that selenium, sulfur, and oxygen present very similar physical and chemical properties in many aspects. However, overall, sulfur and oxygen substituted molecules presented higher binding affinities except for compound 3f.…”

2,1,3‐Benzothiadiazole and Derivatives: Synthesis, Properties, Reactions, and Applications in Light Technology of Small Molecules

“…In the same year, a polymeric derivative was used as a multicolor sensor for DNA detection and quantification 125. Very recently, by using docking and molecular dynamics simulations, the intercalative mode upon DNA binding for compounds 165a – c with perfect agreement with experimental results was independently demonstrated 124c. Theoretical simulations showed that the presence of ethynyl spacers (necessary for intercalation124a,124b) in the ligand stabilizes the intercalation binding mode and yields strong interactions with a modified canonical oligonucleotide (to simulate the dsDNA ambient) with large residence times 124c…”

Designed non‐symmetrical 4,7‐pi‐extended‐2,1,3‐benzothiadiazole derivatives: Synthesis guided by DFT predictions

“…Theoretical approaches for studying BTD derivatives have already given important insights on the comprehension of some properties of those π‐extended compounds . For long, it is known that most of the photophysical properties of such derivatives can be tuned by controlling both the bad gap (HOMO/ LUMO difference) and dipole moments, which are the characteristics with direct effects on the properties of those systems, as already reviewed .…”

“…Theoretical approaches for studying BTD derivatives have already given important insights on the comprehension of some properties of those π-extended compounds. [2][3][4][5][6][7][8] For long, it is known that most of the photophysical properties of such derivatives can be tuned by controlling both the bad gap (HOMO/ LUMO difference) and dipole moments, [9] which are the characteristics with direct effects on the properties of those systems, as already reviewed. [10,11] We have, for instance, investigated the origin of the single emission from a nonsymmetrical fluorescent atropoisomeric BTD molecule (Scheme 1), mostly on the basis of DFT analyses of both ground and excited states.…”