Potential protein kinase inhibitors that target G-quadruplex DNA structures in the human telomeric regions.

Telomeric regions contain Guanine-rich sequences arranged in a planar manner and connected by Hoogsteen hydrogen bonds that can fold into G-quadruplex (G4) DNA structures, and can be stabilized by monovalent metal cations. The presence of G4 DNA holds significance in cancer-related processes, especially due to their regulatory potential at transcriptional and translational levels of oncogene and tumor suppressor genes. The objective of this current research is to explore the evolving realm of FDA-approved protein kinase inhibitors, with a specific emphasis on their capacity to stabilize the G4 DNA structures formed at the human telomeric regions. This involves investigating the possibility of repurposing FDA-approved protein kinase inhibitors as a novel approach for targeting multiple cancer types. In this context, we have selected 16 telomeric G4 DNA structures as targets and 71 FDA-approved small-molecule protein kinase inhibitors as ligands. To investigate their binding affinities, molecular docking of human telomeric G4 DNA with nuclear protein kinase inhibitors and their corresponding co-crystalized ligands were performed. We found that Ponatinib and Lapatinib interact with all the selected G4 targets, the binding free energy calculations, and molecular dynamic simulations confirm their binding efficacy and stability. Thus, it is hypothesized that Ponatinib and Lapatinib may stabilize human telomeric G4 DNA in addition to their ability to inhibit BCR-ABL and the other members of the EGFR family. As a result, we also hypothesize that the stabilization of G4 DNA might represent an additional underlying mechanism contributing to their efficacy in exerting anti-cancer effects.

Targeting AFP-RARß complex formation: a potential strategy for treating AFP-positive hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is a glycoprotein primarily expressed during embryogenesis, with declining levels postnatally. Elevated AFP levels correlate with pathological conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recent investigations underscore AFP's intracellular role in HCC progression, wherein it forms complexes with proteins like Phosphatase and tensin homolog (PTEN), Caspase 3 (CASP3), and Retinoic acid receptors and Retinoid X receptors (RAR/RXR). RAR and RXR regulate gene expression linked to cell death and tumorigenesis in normal physiology. AFP impedes RAR/RXR dimerization, nuclear translocation, and function, promoting gene expression favoring cancer progression in HCC that provoked us to target AFP as a drug candidate. Despite extensive studies, inhibitors targeting AFP to disrupt complex formation and activities remain scarce. In this study, employing protein-protein docking, amino acid residues involved in AFP-RARß interaction were identified, guiding the definition of AFP's active site for potential inhibitor screening. Currently, kinase inhibitors play a significant role in cancer treatment and, the present study explores the potential of repurposing FDA-approved protein kinase inhibitors to target AFP. Molecular docking with kinase inhibitors revealed Lapatinib as a candidate drug of the AFP-RARß complex. Molecular dynamics simulations and binding energy calculations, employing Mechanic/Poisson-Boltzmann Surface Area (MM-PBSA), confirmed Lapatinib's stability with AFP. The study suggests Lapatinib's potential in disrupting the AFP-RARß complex, providing a promising avenue for treating molecularly stratified AFP-positive HCC or its early stages.

A modified method for efficient RNA isolation from mangrove root tissues rich in secondary metabolites.

Secondary metabolites in mangroves often interfere with RNA extraction yielding poor concentration and quality, which is unsuitable for downstream applications. As existing protocols yielded low-quality RNA from root tissues of Kandelia candel (L.) Druce and Rhizophora mucronata Lam., an optimized method was developed for improving the quality and yield of RNA. Compared with three other methods, this optimized protocol gave better RNA yield and purity for both species. The absorbance ratios were ≥1.9 for A260/280 and A260/230, while RNA integrity number values ranged from 7.5 to 9.6. Results show that our modified method is efficient in obtaining high-quality RNA from mangrove roots and is suitable for downstream experiments such as cDNA synthesis, real-time quantitative PCR and next-generation sequencing.

In-silico studies of Brassica oleracea active compounds and their role in thyroid peroxidase activity.

Cabbage, a leafy vegetable that is widely consumed across the globe, holds a significant place within the Brassica family. For almost a century, its potential anti-thyroid effects have captured attention. The presence of compounds such as thiocyanate and goitrin in cabbage has been extensively investigated for their ability to impede sodium-iodide symporter and thyroid peroxidase (TPO) activities. The present study is focused on uncovering the active constituents in cabbage that could interact with TPO, while also examining their stability under cooking temperatures. Employing molecular docking and molecular dynamic simulation techniques, we quantified the binding strength of phytochemicals present in cabbage with the target. Out of the 60 compounds identified in cabbage leaves, only 18 exhibited docking scores surpassing those of the commercially available anti-thyroid drug, methimazole. These chosen compounds were studied for binding free energy and pharmacokinetic properties. A specific compound, gamma-Terpinene, classified as a monoterpene, emerged as noteworthy due to its alignment with all criteria and the highest observed binding free energy compared to others. Furthermore, we explored the stability of gamma-Terpinene at 373.15K (cooking temperature) and observed its susceptibility to degradation. This might contribute to the relatively diminished anti-thyroid effects of cabbage when consumed in cooked form. Consequently, our findings suggest that the consumption of cooked cabbage could be more conducive to maintaining normal thyroid function, as opposed to its raw counterpart.Communicated by Ramaswamy H. Sarma.