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Quinoline derivatives are important heterocyclic compounds with potential medicinal values, especially for treating cancers like breast cancer. However, drug resistance and potential toxicity can limit their effectiveness. New derivatives are needed to specifically target cancer cells, particularly in breast cancer, while minimizing harm to normal cells and side effects for better treatment outcomes. Thus, this study aims to design and synthesize novel quinoline derivatives incorporating substituted piperazine moieties to enhance their anticancer efficacy by inhibiting EGFR, a key therapeutic target for breast cancer. Therefore, in this study, structural elucidation of the synthesized compounds was confirmed by using various analytical techniques, including IR, MASS, and NMR spectral data. Subsequently, these analogs were analyzed for their binding affinity using the molecular docking study, while anticancer efficacy was evaluated against MCF-7 cell lines, followed by an in vivo study in a DMBA-induced rat model. Initially, docking studies of synthesized analogs (8a–i) at the ATP binding site of the EGFR showed better docking scores and MM/GBSA energy, indicating their increased binding affinity to the EGFR. Further, the in vitro evaluation of all compounds (8a–i) showed that the compounds effectively inhibit the EGFR-TK enzyme, with compound 8i showing the highest potency at 87.5%. Moreover, the anti-breast cancer efficacy of compound 8i is attributed to electron-donating groups, which enhance interactions with biological targets. Compound 8i exhibited promising anti-breast cancer activity and was confirmed in vitro and in vivo studies, warranting further investigation as a potential anticancer property.

BackgroundHNF1A is an essential component of the transcription factor network that controls pancreatic β-cell differentiation, maintenance, and glucose stimulated insulin secretion (GSIS). A continuum of protein malfunction is caused by variations in the HNF1A gene, from severe loss-of-function (LOF) variants that cause the highly penetrant Maturity Onset Diabetes of the Young (MODY) to milder LOF variants that are far less penetrant but impart a population-wide risk of type 2 diabetes that is up to five times higher. Before classifying and reporting the discovered variations as relevant in clinical diagnosis, a critical review is required. Functional investigations offer substantial support for classifying a variant as pathogenic, or otherwise as advised by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) ACMG/AMP criteria for variant interpretation.ObjectiveTo determine the molecular basis for the variations in the HNF1A gene found in patients with monogenic diabetes in India.MethodsWe performed functional protein analyses such as transactivation, protein expression, DNA binding, nuclear localization, and glucose stimulated insulin secretion (GSIS) assay, along with structural prediction analysis for 14 HNF1A variants found in 20 patients with monogenic diabetes.ResultsOf the 14 variants, 4 (28.6%) were interpreted as pathogenic, 6 (42.8%) as likely pathogenic, 3 (21.4%) as variants of uncertain significance, and 1 (7.14%) as benign. Patients harboring the pathogenic/likely pathogenic variants were able to successfully switch from insulin to sulfonylureas (SU) making these variants clinically actionable.ConclusionOur findings are the first to show the need of using additive scores during molecular characterization for accurate pathogenicity evaluations of HNF1A variants in precision medicine.

Blumea lacera (Burm.f.) DC. (Asteraceae) is used in the traditional system of medicine for the treatment of inflammation or irritable bowel disease (IBD). In this study, B. lacera was collected from different geographical regions and oil was extracted by hydro-distillation and further chemo-profiled using GC-FID-MS. The major compounds identified were 2,5-dimethoxy-p-cymene (28.7–0.4%), β-caryophyllene (25.5–0.5%), carvotanacetone (24.5–0.4%), chrysanthenone (21.9–9.8%) and 2,6-dimethyl phenol (11.4–1.8%). The constituents of B. lacera also showed marked qualitative and quantitative variations. The percent chemical similarity was observed to be in the range of 51.7% to 59.2% between the localities. Moreover, molecular modelling, membrane molecular dynamics simulations, target prediction were implemented to decipher the potential targets relevant to IBD. This inferred that all these major compounds could be potential drug moieties for treating IBD in terms of targeting h5HTR3A, thereby substantiating the traditional use of B. lacera for the treatment of IBD ailments. [ABSTRACT FROM AUTHOR]

The biosynthetic arginine decarboxylase in Thermus thermophilus is responsible for producing spermidine, a polyamine with numerous biological applications in humans. The arginine decarboxylase has significant applications in biotechnology industries, suggesting the need to evaluate its biochemical and biophysical characteristics at the molecular level. In this study, both in vitro and in silico methods were employed to investigate the structural and functional behavior of the arginine decarboxylase protein. In in vitro, MALDI-TOF, size exclusion, and assay studies were performed to examine the nature and activity of the protein. The MALDI-TOF analysis confirmed the purified protein as biosynthetic arginine decarboxylase. The assay results revealed that the Pyridoxal 5'-Phosphate (PLP) cofactor plays a crucial role in enhancing enzyme activity by producing agmatine (a by-product of spermidine). Further, optimum enzyme activity was observed at 50 °C, suggesting the extremophilic nature of the enzyme. Unlike other proteins, this enzyme displayed optimal activity at both acidic and basic pH, demonstrating its sensitivity to pH changes. Furthermore, the addition of divalent ions like Mg 2+ increased the rate of reaction. In in silico , structure modeling, and comparative molecular dynamics simulation studies were used to assess the protein stability and behavior at different pH and temperature conditions. The findings of this study could be applied to improve enzyme production in the industry.Communicated by Ramaswamy H. Sarma.

Toxoplasma gondii an obligate intracellular parasite causes toxoplasmosis in homeothermic animals. Host invasion of this parasite is mediated by the formation of Moving Junction (MJ) complex which encompasses a network of microneme and Rhoptry Neck proteins (RONs) 2/4/5/8. Among these proteins, RON4 is the only cytosolic secretory protein that is considered as a crucial member, as it directly facilitates the motility of MJ complex by interacting with host tubulin. It is also prominently localized at the host-pathogen interface during the invasion, thus projecting it as a potential drug target. The structure of RON4 is yet to be crystallized. Hence, in this study, fold recognition and Free Energy Landscape sampling was performed to predict the plausible 3D structure of RON4. Further, its interacting pattern with the reported crystal structure of human tubulin was analyzed using molecular docking. Subsequently, a β-tubulin based inhibitory peptides were derived based on its interacting interface observed in RON4-β-tubulin docked complex. Following which, a stepwise validation of these peptides for various physico-chemical properties and its homology with antimicrobial peptides were also screened. The peptide (RT_pep) surpassing all these validation filters was modeled and its stability was analysed by Molecular Dynamics simulation. To validate further, the stable conformation of the RT_pep was docked to RON4. Finally, essential molecular dynamics simulation was conducted to determine the stability and atomic motions of native RON4 and also to decipher its association with β-tubulin and RT_pep. All these analyses cumulatively suggest the therapeutic potential of RT_pep in targeting toxoplasmosis., (© 2017 Wiley Periodicals, Inc.)