Expanding the therapeutic arsenal against cancer: a computational investigation of hybrid xanthone derivatives as selective Topoisomerase 2α ATPase inhibitors.

The DNA topoisomerase II (topo II) enzyme plays an important role in the replication, recombination, and repair of DNA. Despite their widespread applications in cancer therapy, new, selective, and potent topo II inhibitors with better pharmaceutical profiles are needed to handle drug resistance and severe adverse effects. In this respect, an array of 36 new anticancer compounds was designed based on a Xanthone core tethered to multifunctional Pyridine-amines and Imidazole scaffold via alkyl chain linkers. An integrated in silico approach was used to understand the structural basis and mechanism of inhibition of the hybrid xanthone derivatives. In this study, we established an initial virtual screening workflow based on pharmacophore mapping, docking, and cancer target association to validate the target selection process. Next, a simulation-based docking was conducted along with pharmacokinetic analysis to filter out the five best compounds (7, 10, 25, 27, and 30) having binding energies within the range of -60.45 to -40.97 kcal/mol. The screened compounds were further subjected to molecular dynamics simulation for 200 ns followed by MM-GBSA and ligand properties analysis to assess the stability and binding affinity to hTOP2α. The top-ranking hits 3,7-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one (ligand 7) and 3,8-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one (ligand 25) were found to have no toxicity, optimum pharmacokinetic and, DFT properties and stable intermolecular interactions with the active site of hTopo IIα protein. In conclusion, further in vitro and in vivo experimental validation of the identified lead molecules is warranted for the discovery of new human Topoisomerase 2 alpha inhibitors.Communicated by Ramaswamy H. Sarma.

Identification of novel dual acting ligands targeting the adenosine A2A and serotonin 5-HT1A receptors.

GPCRs are a family of transmembrane receptors that are profoundly linked to various neurological disorders, among which is Parkinson's disease (PD). PD is the second most ubiquitous neurological disorder after Alzheimer's disease, characterized by the depletion of dopamine in the central nervous system due to the impairment of dopaminergic neurons, leading to involuntary movements or dyskinesia. The current standard of care for PD is Levodopa, a dopamine precursor, yet the chronic use of this agent can exacerbate motor symptoms. Recent studies have investigated the effects of combining A2AR antagonist and 5-HT1A agonist on dyskinesia and motor complications in animal models of PD. It has been proved that the drug combination has significantly improved involuntary movements while maintaining motor activity, highlighting as a result new lines of therapy for PD treatments, through the regulation of both receptors. Using a combination of ligand-based pharmacophore modelling, virtual screening, and molecular dynamics simulation, this study intends on identifying potential dual-target compounds from IBScreen. Results showed that the selected models displayed good enrichment metrics with a near perfect receiver operator characteristic (ROC) and Area under the accumulation curve (AUAC) values, signifying that the models are both specific and sensitive. Molecular docking and ADMET analysis revealed that STOCK2N-00171 could be potentially active against A2AR and 5-HT1A. Post-MD analysis confirmed that the ligand exhibits a stable behavior throughout the simulation while maintaining crucial interactions. These results imply that STOCK2N-00171 can serve as a blueprint for the design of novel and effective dual-acting ligands targeting A2AR and 5-HT1A.Communicated by Ramaswamy H. Sarma.

Are iron ore microparticles toxic for the European clam Ruditapes decussatus? Response elements from biomarker activities and in silico modeling.

Inevitably, high concentrations of iron, the most widely produced ore globally, can be found in aquatic environments. To assess the toxicity of iron on aquatic organisms, Ruditapes decussatus specimens were subjected to microparticles derived from two types of iron ore (hematite and magnetite) at four different concentrations (0.5, 1, 1.5, and 5 g/L). The findings revealed that both types of iron ore were absorbed by clams in a concentration-dependent manner. Biomarkers analysis demonstrated significant and organ-specific impacts on the health of the clams caused by these microparticles, which was further supported by computational analyses on bioavailability. Within seven days of exposure, changes were observed in the activities of several enzymes, including catalase, acetylcholinesterase, and glutathione S-transferases, as well as in the rate of lipid peroxidation in both the digestive gland and gills. This study provides an environmental perspective on the toxicological effects of iron ore microparticles.

Protective effect of Salvia hispanica (chia seeds) against obesity induced ovarian disorders in rat model.

The main goal of the current report is to assess the protective impacts of chia seeds against obesity-induced ovarian dysfunctions with a trial to elucidate the mechanism of action. Forty rats were divided into 4 groups including lean untreated, lean consuming chia seeds, obese untreated, and rats consumed high-fat diet (HFD) mixed with ground chia seeds for 10 weeks. Anthropometric measures including visceral fat, peri-ovarian fat, ovarian weights, and duration of the estrous cycle were computed. Serum luteinizing (LH), follicular stimulating (FSH), progesterone, estradiol hormones, and tumor necrosis-α (TNF-α) were estimated. Ovarian histopathology and immunohistochemistry (CD31) were performed. Results showed that chia seeds clearly reduced obesity and induced alteration in anthropometric measures with a clear increase in LH and progesterone. Such seeds notably reversed histopathological alteration and reduced TNF-α, and CD31 induced by HFD. Conclusively, chia seeds have a potential protective role against obesity-induced ovarian dysfunction owing to their anti-inflammatory properties.