Spectroscopic and Molecular Dynamics Aspect of Antimalarial Drug Hydroxychloroquine Binding with Human Telomeric G-Quadruplex

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

doi:10.1021/acs.jpcb.2c03267

Cited by 11 publications

(21 citation statements)

References 50 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The CD spectra of htel annealed in 10% and 20% PEG 200 are distinctly different from those of the buffer case as they depict the positive ellipticity around ∼290 and ∼250 nm along with the slight negative ellipticity around ∼260 nm. The feature of the CD spectra of htel is similar to that of the NaCl salt (Figure S2a) which forms antiparallel Gq, suggesting that 10% and 20% PEG fold htel into the antiparallel type Gq structure. With a further increase in the content (40% and 60%) of PEG 200, the feature of the CD spectra changes significantly as the peak of the positive ellipticity at 260 nm increases along with a feature at 240 nm of negative ellipticity with a subsequent decrease in the 290 nm peak as observed in the case of 10% and 20% PEG.…”

supporting

confidence: 66%

“…With a further increase in the content (40% and 60%) of PEG 200, the feature of the CD spectra changes significantly as the peak of the positive ellipticity at 260 nm increases along with a feature at 240 nm of negative ellipticity with a subsequent decrease in the 290 nm peak as observed in the case of 10% and 20% PEG. The observed spectral features of the CD spectra of htel in the case of 40% and 60% PEG 200 are similar to those of the parallel form of Gq (Figure S2b) as observed in many promoter G-rich sequences, 25,26 suggesting that the increased content of PEG 200 induces a conformational change in the htel Gq from the antiparallel to parallel topology. An increase in the crowder concentration probably alters the loop orientation that drives the overall conformation of Gq into the parallel topology.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Chemical Interaction Regulates the Folding and Topology of the G-Quadruplex Exclusively Induced by a Crowder

Bisoi

Singh

2023

J. Phys. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

The folding and stability of G-quadruplexes (Gq) are correlated with cancer and depend significantly on the chemical environment. Crowders are an important constituent of living cells. However, an understanding of the folding and topology of Gq induced exclusively by a crowder is lacking. Hence, folding and stabilization of the human telomere (htel) induced by polyethylene glycol and its derivative crowders have been studied using different biophysical techniques without the addition of salt. The data suggest that the crowder can alone induce the folding of the htel sequence into Gq and the topology of the folded structure depends on the composition of the crowder. Interestingly, a small chain size crowder favors the folding of the htel duplex to Gq, whereas a larger crowder prefers to stabilize the duplex form. Thermochemical data suggest that the nonlinear trend of the stability of folded Gq is modulated mainly by hydrogen bonding between the flexible part of the crowder and nucleobases, and the role of the excluded volume is not prominent. These findings might play an important role in improving our understanding of the folding and stabilization of htel in complex bimolecular environments.

show abstract

supporting

confidence: 66%

mentioning

confidence: 99%

Chemical Interaction Regulates the Folding and Topology of the G-Quadruplex Exclusively Induced by a Crowder

Bisoi

Singh

2023

J. Phys. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

show abstract

“…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%

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

et al. 2023

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…There is a possibility of hydrogen bonding between HCQ and the nucleobases in the quartet and loop regions of htel which may trigger the folding process. 29 However, an extensive molecular dynamic simulation will be useful in getting the detailed mechanism.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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

2023

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Spectroscopic and Molecular Dynamics Aspect of Antimalarial Drug Hydroxychloroquine Binding with Human Telomeric G-Quadruplex

Cited by 11 publications

References 50 publications

Chemical Interaction Regulates the Folding and Topology of the G-Quadruplex Exclusively Induced by a Crowder

Chemical Interaction Regulates the Folding and Topology of the G-Quadruplex Exclusively Induced by a Crowder

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

Contact Info

Product

Resources

About