Rheumatoid arthritis-associated complications during pregnancy and its effect on offspring: comprehensive review.

This study comprehensively explores the complexities of rheumatoid arthritis during pregnancy and its impact on offspring. Through an extensive review of existing literature, we investigate maternal and fetal risks, including adverse pregnancy outcomes and developmental issues in offspring. Utilizing reputable databases such as PubMed, Google Scholar, and Science Direct, we meticulously examined studies exploring the connection between rheumatoid arthritis and pregnancy complications, with a focus on outcomes for offspring. We excluded studies lacking sufficient data or peer review. Synthesizing findings from selected studies, we identified common themes and patterns, presenting results in a clear, organized manner. Our examination reveals a heightened likelihood of preterm birth and preeclampsia among pregnant individuals with rheumatoid arthritis, often correlated with disease activity. Furthermore, we highlight the impact on fetal and neonatal outcomes, such as low birth weight, underscoring the importance of meticulous disease management throughout pregnancy. Balancing the necessity of disease-modifying agents with potential risks, and consideration of medication safety is paramount. A multidisciplinary approach involving rheumatologists and obstetricians is crucial for optimizing outcomes. In conclusion, this synthesis underscores the nuanced challenges of rheumatoid arthritis in pregnancy. A comprehensive understanding and personalized, multidisciplinary approach to an organization is essential for informed decision-making in clinical practice. Our review contributes to ongoing discourse, providing insights for enhanced patient care and guiding future research endeavors.

An assessment of EGFR and HER2 inhibitors with structure activity relationship of fused pyrimidine derivatives for breast cancer: a brief review.

Epidermal growth factor receptor (EGFR) and its subtype human epidermal growth factor receptor 2 (HER2) gets activated when its endogenous ligand(s) bind to its ATP binding site of target receptors. In breast cancer (BC), EGFR and HER2 are two proteins are overexpressed which leads to overexpression of cells proliferation and decreases cell death/apoptosis. Pyrimidine is one of the most widely studied heterocyclic scaffolds for EGFR as well as HER2 inhibition. We gather some remarkable results for fused-pyrimidine derivatives on various cancerous cell lines (in-vitro) and animal (in-vivo) evaluation to highlight their potency. The heterocyclic (five, six-membered, etc.) moieties which are coupled with pyrimidine moiety are potent against EGFR and HER2 inhibitions. Hence structure-activity relationship (SAR) plays important role in study of heterocyclic moiety along pyrimidine and effects of substituents, groups for increase or decrease in the cancerous activity and toxicity. By thoughtful of fused pyrimidines SAR study, it facilitates in receiving excellent overview of the compounds by concerning of efficacy and potential summary for future EGFR inhibitors. Furthermore, we studied the in-silico interactions of synthesized compounds to evaluate binding affinity towards the key amino acids..Communicated by Ramaswamy H. Sarma.

An updated literature on BRAF inhibitors (2018-2023).

BRAF is the most common serine-threonine protein kinase and regulates signal transduction from RAS to MEK inside the cell. The BRAF is a highly active isoform of RAF kinase. BRAF has two domains such as regulatory and kinase domains. The BRAF inhibitors bind in the c-terminus of the kinase domain and inhibit the downstream pathways. The mutation occurs mainly in the A-loop of the kinase domain. The mutation occurs due to a conversion of valine to glutamate/lysine/arginine/aspartic acid at 600th position. Among the diverse mutations, BRAFV600E is the most common and responsible for numerous cancer such as melanoma, colorectal, ovarian, and thyroid cancer. Due to mutations in RAC1, loss of PTEN, NF1, CCND1, USP28-FBW7 complex, COT overexpression, and CCND1 amplification, the BRAF kinase enzyme developed resistance over the commercially available BRAF inhibitors. There is still unmute urgence for the development of BRAF inhibitors to overcome the persistent limitation such as resistance, mutation, and adverse effects of drugs. In the current study, we described the structure, activation, downstream signaling pathway, and mutation of BRAF. Our group also provided a detailed review of BRAF inhibitors from the last five years (2018-2023) highlighting the structure-activity relationship, mechanistic study, and molecular docking studies. We hope that the current analysis will be a useful resource for researchers and provide chemists a glimpse into the future as design and development of more effective and secure BRAF kinase inhibitors. The development of BRAF inhibitors to overcome the persistent limitation such as resistance, mutation, and adverse effects of drugs. In depth description about different heterocyclic scaffolds (quinoline, imidazole, pyridine, triazole, pyrrole etc.) as BRAF inhibitors from the last five years (2018-2023) highlighting the structure-activity relationship, mechanistic study, and molecular docking studies.

Discovery of potential Aurora-A kinase inhibitors by 3D QSAR pharmacophore modeling, virtual screening, docking, and MD simulation studies.

The Aurora-kinase family comprises of cell cycle-regulated serine/threonine kinases playing a vital role during mitosis. Aurora-A kinase is involved in multiple mitotic events in cell cycle and is a major regulator of centrosome function during mitosis. Aurora-A is overexpressed in breast, lung, colon, ovarian, glial, and pancreatic cancer. Hence, Aurora-A kinase is a promising target in cancer therapy. In our current study, a four-point 3D QSAR pharmacophore model has been generated using substituted pyrimidine class of Aurora-A kinase inhibitors. It had a fixed cost value 88.7429. The model mapped well to the external test set comprising of clinically active molecules, with a correlation coefficient r = 0.99. From the mapping, it was found that the hydrophobic features (HY) of a molecule play an important role for Aurora-A kinase inhibitory activity, whereas the ring aromatic feature provides geometric constraint for spatial alignment of different functional group. The hypothesis, with one hydrogen bond acceptor, two ring aromatic features, and one hydrophobic feature, was selected to screen miniMaybridge database. The screened ligands were filtered on the basis of activity, shape, and drug likeliness. This led to the identification of five top hits. These identified potential leads were further subjected to docking with the ATP-binding site of Aurora-A kinase. The molecular dynamic simulation studies of top lead molecules having diverse scaffolds endorsed that the identified molecules had distinctive ability to inhibit Aurora-A kinase. Thus, this study may facilitate the medicinal chemists to design promising ligands with various scaffolds to inhibit Aurora-A kinase. Communicated by Ramaswamy H. Sarma.

Molecular docking and molecular dynamic studies: screening of phytochemicals against EGFR, HER2, estrogen and NF-KB receptors for their potential use in breast cancer.

Breast cancer (BC) is a second common malignancy in female globally. Hence, identification of novel therapeutic agents is extremely important. Molecular docking and MD simulation are the important tools in the process of drug discovery for searching the potential hits. The structure-based drug designing technique also reveals the information about ligands behavior in computational environment. Docking tools help in visualization and analysis of protein-ligand complex at atomic level. Molecular dynamics shows the stability of the molecules in the receptor cavity in the simulated environment. In this research work, we have screened potent phytochemicals against the BC. We docked the phytochemicals and examined the binding affinities of ligands towards the EGFR, HER2, estrogen and NF-κB receptors. Pristimerin, ixocarpalactone A, viscosalactone B and zhankuic acid A have shown higher binding affinities and energies towards targeted receptors among the screened phytochemicals. MD simulation study shows stability of docked complex for pristimerin and HER2 receptor. These phytochemicals can be repurposed for their anticancer activity. This in-silico work provides a strong ground for further investigation of their anticancer activity.

Management of COVID-19-induced cytokine storm by Keap1-Nrf2 system: a review.

The natural pathway of antioxidant production is mediated through Kelch-like erythroid cell-derived protein with Cap and collar homology [ECH]-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2) system. Keap1 maintains a low level of Nrf2 by holding it in its protein complex. Also, Keap1 facilitates the degradation of Nrf2 by ubiquitination. In other words, Keap1 is a down-regulator of Nrf2. To boost the production of biological antioxidants, Keap1 has to be inhibited and Nrf2 has to be released. Liberated Nrf2 is in an unbound state, so it travels to the nucleus to stimulate the antioxidant response element (ARE) present on the antioxidant genes. AREs activate biosynthesis of biological antioxidants through genes responsible for the production of antioxidants. In some cases of coronavirus disease 2019 (COVID-19), there is an enormous release of cytokines. The antioxidant defense mechanism in the body helps in counteracting symptoms induced by the cytokine storm in COVID-19. So, boosting the production of antioxidants is highly desirable in such a condition. In this review article, we have compiled the role of Keap1-Nrf2 system in antioxidant production. We further propose its potential therapeutic use in managing cytokine storm in COVID-19.