New Insights into the Mechanism of Action of the Drug Chloroquine: Direct Interaction with DNA and Cytotoxicity

Rocha, M. S.

doi:10.1021/acs.jpcb.2c01119

Cited by 8 publications

(6 citation statements)

References 58 publications

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“…A recent study [11] has suggested that dsDNA binding by chloroquine may be the reason for its toxicity. Costa et al used OT stretching experiments to characterize chloroquine-DNA intercalative binding.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study examined chloroquine-DNA intercalation with optical tweezers (OTs). However, the applied stretching forces were too low (<1.5 pN) to observe significant chloroquine intercalation under the conditions studied [11]. Here, we performed stretching experiments with our OT instrument under a much broader force and chloroquine concentration range.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of DNA Intercalation by Chloroquine Provides Insights into Toxicity

Joshi,

McCauley,

Morse

et al. 2024

IJMS

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Chloroquine has been used as a potent antimalarial, anticancer drug, and prophylactic. While chloroquine is known to interact with DNA, the details of DNA–ligand interactions have remained unclear. Here we characterize chloroquine–double-stranded DNA binding with four complementary approaches, including optical tweezers, atomic force microscopy, duplex DNA melting measurements, and isothermal titration calorimetry. We show that chloroquine intercalates into double stranded DNA (dsDNA) with a KD ~ 200 µM, and this binding is entropically driven. We propose that chloroquine-induced dsDNA intercalation, which happens in the same concentration range as its observed toxic effects on cells, is responsible for the drug’s cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanism of DNA Intercalation by Chloroquine Provides Insights into Toxicity

Joshi,

McCauley,

Morse

et al. 2024

IJMS

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“…12,13 In a recent study, the interaction of CLQ was studied with nonspecific long DNA, and it was reported that CLQ prefers to intercalate with DNA. 14 CLQ has one quinoline ring along with side chain having two nitrogen atom which gets protonated in the physiological pH (7.4) condition; hence, CLQ is diprotic under physiological pH conditions. Both the quinoline ring and the positive side chain of CLQ have the capability to interact with DNA depending on the nature of nucleobases.…”

Section: ■ Introductionmentioning

confidence: 99%

“…There are few studies in which the binding of CLQ with DNA has been discussed. , It has been proposed that CLQ may bind with DNA through electrostatic interaction as well as intercalation mode. , In a recent study, the interaction of CLQ was studied with nonspecific long DNA, and it was reported that CLQ prefers to intercalate with DNA . CLQ has one quinoline ring along with side chain having two nitrogen atom which gets protonated in the physiological pH (7.4) condition; hence, CLQ is diprotic under physiological pH conditions.…”

Section: Introductionmentioning

confidence: 99%

“…Both the quinoline ring and the positive side chain of CLQ have the capability to interact with DNA depending on the nature of nucleobases. These earlier studies provide utilitarian information about the interaction of CLQ with DNA; however, the molecular level picture about the DNA-drug binding such as the importance of the chemical nature and arrangement of nucleobases of DNA as well as the particular functional group of CLQ responsible for the interaction is almost lacking. The groove as well as intercalator mode of the binding of different chemical molecules with DNA has been studied earlier and has been correlated with the toxicity effect of molecules on DNA. − It is known that the sequence of DNA controls many important biological processes such as replication and transcription, which can play an important role in the action of CLQ .…”

Section: Introductionmentioning

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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Amodiaquine Nonspecifically Binds Double Stranded and Three‐Way Junction DNA Structures

Slavkovic,

Shoara,

Kaiyum

et al. 2024

ChemBioChem

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The 4‐aminoquinoline class of compounds includes the important antimalarial compounds amodiaquine and chloroquine. Despite their medicinal importance, the mode of action of these compounds is poorly understood. In a previous study we observed these compounds, as well as quinine and mefloquine, tightly bind the DNA cocaine‐binding aptamer. Here, we further explore the range of nucleic acid structures bound by these compounds. To gauge a wide range of binding affinities, we used isothermal titration calorimetry to explore high affinity binding (nM to tens of mM) and NMR spectroscopy to assay weak binding biding in the hundreds of micromolar range. We find that amodiaquine tightly binds all double stranded DNA structures explored. Mefloquine binds double stranded DNA duplex molecules tightly and weakly associates with a three‐way junction DNA construct. Quinine and chloroquine only weakly bind duplex DNA but do not tightly bind any of the DNA constructs explored. A simulation of the free energy of binding of these ligands to the Dickerson‐Drew dodecamer resulted in an excellent agreement between the simulated and experimental free energy.These results provide new insight into the DNA binding of clinically important antimalarial compounds and may play a role in future development of new antimalarials.

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New Insights into the Mechanism of Action of the Drug Chloroquine: Direct Interaction with DNA and Cytotoxicity

Cited by 8 publications

References 58 publications

Mechanism of DNA Intercalation by Chloroquine Provides Insights into Toxicity

Mechanism of DNA Intercalation by Chloroquine Provides Insights into Toxicity

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

Amodiaquine Nonspecifically Binds Double Stranded and Three‐Way Junction DNA Structures

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