Hydroxychloroquine (HCQ) is an important drug that is in the trial stage for different types of cancer diseases; however, insight about the mechanism of its action is almost unknown. G-quadruplex (Gq) has been considered one of the potential targets for the cure of cancer; hence, it is essential to understand the possibility of the binding of HCQ with Gq to get a better understanding of its action. In this study, the molecular insight into the possibility of the binding of HCQ with different topological forms of Gq of the human telomere (htel) has been investigated using spectroscopic, thermochemical, and molecular dynamics simulation techniques. The spectroscopic and thermochemical studies clearly suggest that HCQ has a topological preference in the binding with htel in the form of a hybrid structure rather than the antiparallel form and the binding of HCQ stabilizes preferably to the hybrid form. The molecular dynamics simulation study suggests that the interaction of HCQ in the groove and loop regions of the hybrid structure is more stable compared to the antiparallel form, which is the probable reason for the topological preference of HCQ. This study depicts that HCQ has a topological preference in the binding and stabilization of the Gq of htel, which makes it potentially an important drug for targeting the telomere region associated with cancer disease.
Hydroxychloroquine (HCQ) is an important antimalarial drug which functions plausibly by targeting the DNA of parasites. Salts play a crucial role in the functionality of various biological processes. Hence, the effect of salts (NaCl and MgCl2) on the binding of HCQ with AT- and CG-DNAs as well as the binding-induced stability of both sequences of DNAs have been investigated using the spectroscopic and molecular dynamics (MD) simulation methods. It has been found that the effect of salts on the binding of HCQ is highly sensitive to the nature of ions as well as DNA sequences. The effect of ions is opposite for the binding of AT- and CG-DNAs as the presence of Mg2+ ions enhances the binding of HCQ with AT-DNA, whereas the binding of HCQ with CG-DNA gets decreased on the addition of both ions. Similarly, the presence of Mg2+ enhances the stabilization of HCQ-bound AT-DNA, whereas the effect is opposite for the CG-DNA in the presence of both the ions. The MD simulation study suggests that the hydration states of both ions are different and they interact differently in the minor and major grooves of both the sequences of DNA which may be one of the reasons for the different binding of HCQ with these two sequences of DNA in the presence of salts. The information about the effect of salts on the binding of HCQ with DNAs in a sequence-specific manner may be useful in understanding the mechanism of the action and toxicity effect of HCQ against malaria.
Interfacial water associated with phospholipids plays an important role in different biological processes such as fibrillation of disordered protein, neurotransmitter interaction with lipids, and hydrated proton translocation.However, understanding the structural change of interfacial water and phospholipids during these biological processes is difficult due to the lack of appropriate selective technique and soft nature of these interfaces. Vibrational sum-frequency generation (VSFG) is a second-order nonlinear spectroscopic technique, which has the inherent surface selectivity as well as sensitivity and hence has been utilized to understand the properties of interfaces. In this review, the utilization of VSFG technique has been discussed in understanding the structural change of interfacial water and lipids during several biological processes.
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.
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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