Protein-protein interaction and interference of carcinogenesis by supramolecular modifications.

Protein-protein interactions (PPIs) are essential in normal biological processes, but they can become disrupted or imbalanced in cancer. Various technological advancements have led to an increase in the number of PPI inhibitors, which target hubs in cancer cell's protein networks. However, it remains difficult to develop PPI inhibitors with desired potency and specificity. Supramolecular chemistry has only lately become recognized as a promising method to modify protein activities. In this review, we highlight recent advances in the use of supramolecular modification approaches in cancer therapy. We make special note of efforts to apply supramolecular modifications, such as molecular tweezers, to targeting the nuclear export signal (NES), which can be used to attenuate signaling processes in carcinogenesis. Finally, we discuss the strengths and weaknesses of using supramolecular approaches to targeting PPIs.

Discovery of putative inhibitors against main drivers of SARS-CoV-2 infection: Insight from quantum mechanical evaluation and molecular modeling.

SARS-CoV-2 triggered a worldwide medical crisis, affecting the world's social, emotional, physical, and economic equilibrium. However, treatment choices and targets for finding a solution to COVID-19's threat are becoming limited. A viable approach to combating the threat of COVID-19 is by unraveling newer pharmacological and therapeutic targets pertinent in the viral survival and adaptive mechanisms within the host biological milieu which in turn provides the opportunity to discover promising inhibitors against COVID-19. Therefore, using high-throughput virtual screening, manually curated compounds library from some medicinal plants were screened against four main drivers of SARS-CoV-2 (spike glycoprotein, PLpro, 3CLpro, and RdRp). In addition, molecular docking, Prime MM/GBSA (molecular mechanics/generalized Born surface area) analysis, molecular dynamics (MD) simulation, and drug-likeness screening were performed to identify potential phytodrugs candidates for COVID-19 treatment. In support of these approaches, we used a series of computational modeling approaches to develop therapeutic agents against COVID-19. Out of the screened compounds against the selected SARS-CoV-2 therapeutic targets, only compounds with no violations of Lipinski's rule of five and high binding affinity were considered as potential anti-COVID-19 drugs. However, lonchocarpol A, diplacol, and broussonol E (lead compounds) were recorded as the best compounds that satisfied this requirement, and they demonstrated their highest binding affinity against 3CLpro. Therefore, the 3CLpro target and the three lead compounds were selected for further analysis. Through protein-ligand mapping and interaction profiling, the three lead compounds formed essential interactions such as hydrogen bonds and hydrophobic interactions with amino acid residues at the binding pocket of 3CLpro. The key amino acid residues at the 3CLpro active site participating in the hydrophobic and polar inter/intra molecular interaction were TYR54, PRO52, CYS44, MET49, MET165, CYS145, HIS41, THR26, THR25, GLN189, and THR190. The compounds demonstrated stable protein-ligand complexes in the active site of the target (3CLpro) over a 100 ns simulation period with stable protein-ligand trajectories. Drug-likeness screening shows that the compounds are druggable molecules, and the toxicity descriptors established that the compounds demonstrated a good biosafety profile. Furthermore, the compounds were chemically reactive with promising molecular electron potential properties. Collectively, we propose that the discovered lead compounds may open the way for establishing phytodrugs to manage COVID-19 pandemics and new chemical libraries to prevent COVID-19 entry into the host based on the findings of this computational investigation.

Checkpoints and immunity in cancers: Role of GNG12.

Cancer progression is enhanced through cell proliferation, with the crucial role of the transducer and transmembrane -signal regulator (GNG12) bringing it to the fore. Dysregulation of cancer cell metabolism, evasion of the immune system, cell cycle, apoptosis, and chemoresistance result from inconsistent initiation of the NF-kB signaling pathway. We excerpt from previous studies that overactivation of the canonic NF-kB cascade occurs in varieties of tumor cells, which results in the growth of lymphovascular invasion, as well as neural invasion. Recently, research has adduced that a particular G protein- coupled receptor (GNG12) is silently involved in the activation of the NF-kB signal, which supports the evasion of cancer immunity and in turn activates cancer proliferation, angiogenesis, and immunotherapeutic resistance. While the likely impact of GNG12 in relation to the progression of tumors is being established, there is insufficient knowledge regarding the functions and mechanisms of GNG12 in cancer immunity. Furthermore, the cancer-associated role as well as the clinical correlation of GNG12 have long been unknown; thus, their identification is more likely to pave the path for a novel regime of tumor suppression. In this study, we established the silent role of GNG12 in activating NF-kB genes and the synergism between NF-kB and PD-L1 expression. Captivatingly, we reported that silencing GNG12 gene downregulates the transcription of PD-L1 gene. We therefore suggested that GNG12 is a risk factor for several cancers, and a possible target for immunotherapy.

Overcoming immunotherapeutic resistance in PDAC: SIRPα-CD47 blockade.

A daily increase in the number of new cases of pancreatic ductal adenocarcinoma remains an issue of contention in cancer research. The data revealed that a global cumulated case of about 500, 000 have been reported. This has made PDAC the fourteenth most occurring tumor case in cancer research. Furthermore, PDAC is responsible for about 466,003 deaths annually, representing the seventh prevalent type of cancer mortality. PDAC has no salient symptoms in its early stages. This has exasperated several attempts to produce a perfect therapeutic agent against PDAC. Recently, immunotherapeutic research has shifted focus to the blockade of checkpoint proteins in the management and of some cancers. Investigations have centrally focused on developing therapeutic agents that could at least to a significant extent block the SIRPα-CD47 signaling cascade (a cascade which prevent phagocytosis of tumors by dendritic cells, via the deactivation of innate immunity and subsequently resulting in tumor regression) with minimal side effects. The concept on the blockade of this interaction as a possible mechanism for inhibiting the progression of PDAC is currently being debated. This review examined the structure--function activity of SIRPα-CD47 interaction while discussing in detail the mechanism of tumor resistance in PDAC. Further, this review details how the blockade of SIRPα-CD47 interaction serve as a therapeutic option in the management of PDAC.

Structure-based discovery of selective CYP17A1 inhibitors for Castration-resistant prostate cancer treatment.

Prostate cancer (PCa) is the most common malignancy found in men and the second leading cause of cancer-related death worldwide. Castration-resistant PCa (CRPC) is defined by PCa cells that stop responding to hormone therapy. Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) plays a critical role in the biosynthesis of androgens in humans. Androgen signaling cascade is a principal survival pathway for PCa cells and androgen-deprivation therapy (ADT) remains the key treatment for patients marked with locally advanced and metastatic PCa cells. Available synthetic drugs have been reported for toxicity, drug resistance, and decreasing efficacy. Thus, the design of novel selective inhibitors of CYP17A1 lyase would help circumvent associated side effects and improve pharmacological activities. Therefore, we employed structural bioinformatics techniques via molecular docking; molecular mechanics generalized born surface area (MM-GBSA), molecular dynamics (MD) simulation, and pharmacokinetic study to identify putative CYP17A1 lyase inhibitors. The results of the computational investigation showed that the Prunus dulcis compounds exhibited higher binding energy than the clinically approved abiraterone acetate. The stability of the ligand with the highest binding affinity (quercetin-3-o-rutinoside) was observed during MD simulation for 10 ns. Quercetin-3-o-rutinoside was observed to be stable within the active site of CYP17A1Lyase throughout the simulation period. The result of the pharmacokinetic study revealed that these compounds are promising therapeutic agents. Collectively, this study proposed that bioactive compounds from P. dulcis may be potential selective inhibitors of CYP17A1Lyase in CRPC treatments.

Chinese nutraceuticals and physical activity; their role in neurodegenerative tauopathies.

The onset of neurodegenerative disease has not only been a major cause of scientific worry, but of economic burden to the health system. This condition has been further attributed to mis-stability, deletion or mutation of tau protein, causing the onset of Corticobasal degeneration, Pick's diseases, Progressive supranuclear palsy, Argyrophilic grains disease, Alzheimer's diseases etc. as scientifically renowned. This is mainly related to dysregulation of translational machinery, upregulation of proinflammatory cytokines and inhibition of several essential cascades such as ERK signaling cascade, GSK3ß, CREB, and PKA/PKB (Akt) signaling cascades that enhances protein processing, normal protein folding, cognitive function, and microtubule associated tau stability. Administration of some nutrients and/or bioactive compounds has a high tendency to impede tau mediated inflammation at neuronal level. Furthermore, prevention and neutralization of protein misfolding through modulation of microtubule tau stability and prevention of protein misfolding is by virtue few of the numerous beneficial effects of physical activity. Of utmost important in this study is the exploration of promising bioactivities of nutraceuticals found in china and the ameliorating potential of physical activity on tauopathies, while highlighting animal and in vitro studies that have been investigated for comprehensive understanding of its potential and an insight into the effects on human highly probable to tau mediated neurodegeneration.