Contrasting Effect of Salts on the Binding of Antimalarial Drug Hydroxychloroquine with Different Sequences of Duplex DNA

Bisoi, Asim; Sarkar, Sunipa; Singh, Prashant Chandra

doi:10.1021/acs.jpcb.2c02755

Cited by 2 publications

(4 citation statements)

References 40 publications

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“…Phosphate backbone as well as minor and major grooves are three binding sites available in DNA; hence, the binding of any drug molecule with particular sequence may depend on its tendency to accommodate in these binding sites. ,,− In order to understand the accommodation of drug molecules in the groove regions of DNA, a DAPI displacement assay has been performed. The fluorescence intensity of DAPI in buffer gets quenched due to the plausible intramolecular proton transfer from the amidino to the indole moiety (black bar in Figure a and black line in Figures S6 and S7).…”

Section: Resultsmentioning

confidence: 99%

“…46 With the addition of the drug, the fluorescence intensity of DAPI decreases further, which suggests that drug molecules intrude into the major groove and enhance the charge transfer process of DAPI. 31,32 It is noticeable that the change in the fluorescence of DAPI on the addition of drug is more prominent for (CG) 6 than C 6 G 6 , which suggests that CLQ/7CLQ interactions with alternate CG nucleobases are important in its higher binding compared to those with continual CG nucleobases. The change in the fluorescence of DAPI is higher in the case of CLQ than 7CLQ, which suggests that the charged group of CLQ intrudes mainly into the major groove of CG DNA, causing the enhanced binding of CLQ.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…However, the extent of decrease in the fluorescence intensity is notably less for 7CLQ than CLQ which suggests that CLQ may interact strongly with DNA compared to 7CLQ as earlier studies have shown that the decrease in the fluorescence intensity of these drug molecules are associated with DNA binding. 31,32 The decrease in the fluorescence of CLQ depends on the nature of the nucleobases as well as the arrangement of the particular nucleobases in the sequence (Figure 2e). For example, the decrease in the fluorescence intensity of CLQ increases with the replacement of the CG nucleobases in place of AT (minimum intensity drop of CLQ for pure AT sequence and maximum for pure CG sequence).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Nucleobase Specific Understanding about the Interaction of Antimalarial Drug Chloroquine with Duplex DNA

et al. 2023

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Antimalarial action of a drug is closely associated with the interaction with the parasite's DNA. Hence, in this study, the interaction of an important antimalarial drug, chloroquine (CLQ), has been investigated with six different sequences of DNA having pure adenine (A)−thymine (T) and pure cytosine (C)−guanine (G) as well as mixed nucleobases to achieve the nucleobase level of information in the binding of antimalarial drug with DNA along with binding induced stabilization/destabilization of DNA using different spectroscopic methods and molecular dynamics simulation technique. Further, the experiments have been also performed with 4-amino-7-chloroquinoline (7CLQ), an analogue of CLQ, to understand the role of the quinoline ring and side chain of CLQ in the binding with different sequences of DNA. The binding efficiency of CLQ with any sequence of DNA is higher than 7CLQ suggesting that the presence of charge on CLQ plays a prominent role in DNA binding. The data suggest that the binding of drug as well as induced stabilization of DNA depends significantly on the nature as well as the arrangement of the nucleobases. In general, the binding of CLQ with pure CG DNA is higher than with pure AT DNA; moreover, it prefers an alternate order of CG/AT than continual nucleobases in duplex DNA. CLQ predominately accommodates in the minor groove of AT DNA and prefers to form hydrogen bond mostly with the adenine nucleobase. In contrast to AT DNA, CLQ intrudes into the both major and minor grooves, but it is primarily accommodated into the major groove of CG DNA. CLQ forms a hydrogen bond mainly with guanine in the major groove and cytosine in the minor groove of CG DNA which enhances the binding of CLQ compared to AT DNA as well as induces higher stabilization in CG DNA. The molecular level information obtained about the functional group responsible for the interaction of CLQ as well as the role of chemical nature of nucleobases along with its ordering on the binding of CLQ with DNA may be useful in comprehensive understanding of its action mechanism.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Nucleobase Specific Understanding about the Interaction of Antimalarial Drug Chloroquine with Duplex DNA

et al. 2023

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“…The decrease in the emission intensity of drug molecules is slightly higher for htel than other sequences. Based on the earlier studies, it has been suggested that the fluorescence intensity of antimalarial drugs decreases on binding with DNA. ,, The change in the absorbance and fluorescence data suggest that all the Gq-forming sequences of DNA interact with the drugs; however, the propensity of interaction of htel may be different from that of other sequences.…”

Section: Resultsmentioning

confidence: 99%

Antimalarial Drugs Induce the Selective Folding of Human Telomeric G-Quadruplex in a Cancer-Mimicking Microenvironment

2023

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Regulating the equilibrium between the duplex form of DNA and G-quadruplex (Gq) and stabilizing the folded Gq are the critical factors for any drug to be effective in cancer therapy due to the direct involvement of Gq in controlling the transcription process. Antimalarial drugs are in the trial stage for different types of cancer diseases; however, the plausible mechanism of action of these drug molecules is not well known. Hence, we investigate the plausible role of antimalarial drugs in the folding and stabilization of Gq-forming DNA sequences from the telomere and promoter gene regions by varying the salt (KCl) concentrations, mimicking the in vitro cancerous and normal cell microenvironments. The study reveals that antimalarial drugs fold and stabilize specifically to telomere Gq-forming sequences in the cancerous microenvironment than the DNA sequences located in the promoter region of the gene. Antimalarial drugs are not only able to fold Gq but also efficiently protect them from unfolding by their complementary strands, hence significantly biasing the equilibrium toward the Gq formation from the duplex. In contrast, in a normal cell microenvironment, K+ controls the folding of telomeres, and the role of antimalarial drugs is not prominent. This study suggests that the action of antimalarial drugs is sensitive to the cancer microenvironment as well as selective to the Gq-forming region.

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Contrasting Effect of Salts on the Binding of Antimalarial Drug Hydroxychloroquine with Different Sequences of Duplex DNA

Cited by 2 publications

References 40 publications

Nucleobase Specific Understanding about the Interaction of Antimalarial Drug Chloroquine with Duplex DNA

Nucleobase Specific Understanding about the Interaction of Antimalarial Drug Chloroquine with Duplex DNA

Antimalarial Drugs Induce the Selective Folding of Human Telomeric G-Quadruplex in a Cancer-Mimicking Microenvironment

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