Current Topics in Medicinal Chemistry - Volume 21, Issue 31, 2021

The polycomb repressive complex 2 (PRC2) can methylate at lysine 27 of histone H3 at the trimethylation level (H3K27me3). This leads to gene silencing and is known to be dysregulated in many cancers. PRC2 is made up of three core subunits: EZH2, SUZ12, and EED. EED is essential for the regulation of PRC2 function by binding to H3K27me3. Targeting the allosteric site within EED offers new strategies to disrupt the PRC2 activity. In this minireview, we summarize some of the recent developments in small molecules that target EED and its interaction with other core proteins in the PRC2 complex.

Infectious diseases have been evolving and re-evolving over the ages and causing immense misery to humans. Among them, some have been prevented and eradicated, but few are still threatening the modern era since their origin. The majority of these infectious diseases are poverty-driven, hence highly prevalent in the lower-income and mid-income countries of Africa and Asia. The world’s deadliest infections, including Tuberculosis, Malaria and HIV/AIDS, have been considered as the “Big Three” infectious diseases (BTIDs). With leading infections and deaths every year, the BTIDs have been recognized as the world’s greatest pandemics. In light of these alarming situations, this review has been aimed to provide a comprehensive overview of the current status of chemotherapeutics, associated challenges and future perspectives of BTIDs.

Breast cancer (BC) is the second most commonly diagnosed cancer in the world. BC develops due to dysregulation of transcriptional profiles, substantial interpatient variations, genetic mutations, and dysregulation of signaling pathways in breast cells. These events are regulated by many genes such as BRCA1/2, PTEN, TP53, mTOR, TERT, AKT, PI3K and others genes. Treatment options for BC remain a hurdle, which warrants a comprehensive understanding that establishes an interlinking connection between these genes in BC tumorigenesis. Consequently, there is an increasing demand for alternative treatment approaches and the design of more effective treatments. In this regard, it is crucial to build the corresponding transcriptional regulatory networks governing BC by using advanced genetic tools and techniques. In the past, several molecular editing technologies have been used to edit genes with several limitations. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR Associated Protein 9 (CRISPR/Cas9) recently received wise attention due to its potential in biomedical and therapeutic applications. Here, we review the role of various molecular signalling pathways dysregulated in BC development such as PTEN/PI3K/AKT/mTOR as well as BRCA1/BRCA2/TP53/TERT and their interplay between the related gene networks in BC initiation, progression and development of resistance against available targeted therapeutic agents. Use of CRISPR/Cas9 gene-editing technology to generate BC gene-specific transgenic cell lines and animal models to decipher their role and interactions with other gene products has been employed successfully. Moreover, the significance of using CRISPR/Cas9 technology to develop early BC diagnostic tools and treatments is discussed here.

Neurodegeneration is a syndrome that occurs through the loss of the neuronal system's structure and function. In the 21st century, major health issues are related to cognitive impairment and neurological disorders such as autism, learning disabilities, Huntington’s, cerebral palsy, schizophrenia, Alzheimer's, neuromuscular, lateral sclerosis, and Parkinson’s disease may be life-threatening. Various experimental and epidemiological studies reveal the risk factors associated with the disease, like oxidative stress, hypertension, antioxidant enzyme abnormalities, metabolic toxicity, advanced age, cytoskeletal abnormalities, genetic defects, autoimmunity, mineral deficiencies, and other vascular disorders. Various compounds have been screened for the treatment of neurodegenerative diseases (NDs), but, due to their side effects, they have solitary symptomatic benefits. Phytochemicals play a crucial role in maintaining the chemical balance of the brain by affecting the receptor function of specific inhibitory neurotransmitters. This review highlights the importance of phytochemicals for neurodegenerative diseases, in particular the possible mechanism of action of these natural compounds used for the treatment.

Background: Sphingosine kinase 1 (SPhK1) is a crucial signaling enzyme involved in cell proliferation, cellular survival, stimulation of angiogenesis, and apoptosis prevention. Recently, we have reported the unfolding kinetics of SPhK1 using molecular dynamics (MD) simulation, circular dichroism, and fluorescence spectroscopy. We found that SPhK1 showed a biphasic unfolding with an intermediate state (∼ 4.0 M urea). Objective: We aim to understand the impact of MD simulation duration on the structure, function, and dynamics of proteins. In order to get deeper insights into the folding mechanism, an extended MD simulation is required. Methods: Here, we extended the MD simulations time scale from 100 to 300 ns on SPhK1 at increasing urea concentration to explore structural changes in the SPhK1. Results: The results suggested a constant form of the unfolding of SPhK1 upon extending the simulation time scale at different urea concentrations. Furthermore, we showed step by step unfolding and percentage of secondary structure contents in SPhK1 under the influence of urea at each concentration. Conclusion: The results from the current work revealed a uniform pattern of the SPhK1 unfolding at different urea concentrations. This study provides deeper mechanistic insights into the urea-induced denaturation of SPhK1.