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AbstractDespite the exponential increase in research toward better treatment options for breast cancer patients, developing an effective drug with fewer side effects continues to remain a challenge. Natural compounds have emerged as a viable option and several drugs have been derived or inspired from them. In this study, we screened a library of natural compounds with diverse chemical structures against selected kinase proteins using in silicomethods such as molecular docking and dynamics simulation. The best results were obtained between β tetralone and MDM2E3 ubiquitin ligase protein. In vitroexperiments such as cytotoxicity, scratch assays and flow cytometry analysis using an MCF7 cell line were performed to determine the anti-cancer potential of the compound. As the treatment resulted in cell death and apoptosis, β tetralone was screened in silicoagainst anti-apoptotic targets where the best results were obtained between Bcl-w and β tetralone. This comprehensive study suggests that the anti-cancer activity of β tetralone is probably through the dual targeting of MDM2E3 ubiquitin kinase and Bcl-w anti-apoptotic protein.Communicated by Ramaswamy H. Sarma

AbstractMajor cause of mortality in ovarian cancer can be attributed to a lack of specific and sensitive biomarkers for diagnosis and prognosis of the disease. Uncovering the mutations in genes involved in crucial oncogenic pathways is a key step in discovery and development of novel biomarkers. Whole exome sequencing (WES) is a powerful method for the detection of cancer driver mutations. The present work focuses on identifying functionally damaging mutations in patients with high-grade serous ovarian carcinoma (HGSC) through computational analysis of WES. In this study, WES data of HGSC patients was retrieved from the genomic literature available in sequence read archive, the variants were identified and comprehensive structural and functional analysis was performed. Interestingly, I66T and V138I mutations were found to be co-occurring in the IL7R gene in four out of five HGSC patient samples investigated in this study. The V138I mutation was located in the fibronectin type-3 domain and computationally assessed to be causing disruptive effects on the structure and dynamics of IL7R protein. This mutation was found to be co-occurring with the neutral I66T mutation in the same domain which compensated the disruptive effects of V138I variant. These comprehensive studies point to a hitherto unexplored significant role of the IL7R gene in ovarian carcinoma. It is envisaged that the work will lay the foundation for the development of a novel biomarker with potential application in molecular profiling and in estimation of the disease prognosis.Communicated by Ramaswamy H. Sarma

Glycation is the non-enzymatic covalent attachment of a sugar (carbohydrate) to a protein or lipid molecule. This process leads to the formation of advanced glycation end products (AGEs) which bind to the receptor for AGEs (RAGE) and facilitate further disease progression. Understanding the mechanisms for AGE formation in the progression of type 2 diabetes mellitus (T2DM) and neurodegenerative diseases can help target pathways that either facilitate AGE formation or the pathways that upregulate RAGE expression and activation. Several researchers have embarked on targeting these pathways either directly or indirectly. Nanoparticle (NP)–based approaches prove to be advantageous due to their modifiable surface properties, high biocompatibility and bioavailability in the body, minimal side effects and efficient blood–brain barrier permeability. Various drugs or therapeutic components can be encapsulated within them for targeted drug delivery. NPs explored in this study significantly brought down the overall reactive oxygen species (ROS) production, inhibited glycation and further fibrillation of particular proteins and increased cell viability. In this review, we discuss NPs that have shown a significant antiglycation property, ROS scavenging activity and blood–brain barrier permeability along with an ability to inhibit secondary structure changes and aggregation of proteins. However, clinical utility of these NPs still remains unclear as there is no clinical evidence to show that targeting of glycation with NP-based drug delivery systems could be a therapy for T2DM and reduce the risk of associated neurodegenerative diseases. Extensive research related to NPs with antiglycation properties may be a very successful approach for the treatment of T2DM and associated neurodegenerative disorders like Alzheimer’s disease.

The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19–21have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20and 21have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20as a potential clinical candidate.