Cystatins are thiol proteinase inhibitors (TPI), present ubiquitously in animals, plants and micro-organisms. These are not merely inhibitors rather they are at heart of many pathological conditions ...ranging from diabetes to renal failure. These are essential for maintenance of protein balance of the cell; once this balance gets disturbed, it may lead to cell death. Thus, cystatins cannot be merely regarded as TPI’s as these have been found to play a pivotal role in tumorigenesis and neurodegenerative diseases. Many studies have reported the variation in cystatin level in incidences of different types of cancer; highlighting an important role played by these inhibitors in cancer development and progression. Cystatin C is increasingly replacing creatinine as a biomarker of glomerular filtration rate (GFR) thereby highlighting the importance of this important inhibitor. Some recent studies have also reported the interaction pattern of various anti-cancer drugs with cystatins in a bid to find how these drugs affect this important inhibitors and whether these drugs have any side effect on cystatins. Thus, in this growing disease era it can be said that cystatins are no more just inhibitors blocking the activity of thiol proteases rather they play a pivotal role in variety of pathological conditions.
Microtubule affinity regulating kinase (MARK4) is a potential drug target for different types of cancer as it controls the early step of cell division. In this study, we have screened a series of ...natural compounds and finally identified rosmarinic acid (RA) as a potential inhibitor of MARK4. Molecular docking and 500 ns all-atom simulation studies suggested that RA binds to the active site pocket of MARK4, forming enough number of non-covalent interactions with critical residues and MARK4-RA complex is stable throughout the simulation trajectory. RA shows an excellent binding affinity to the MARK4 with a binding constant (K) of 10
M
. Furthermore, RA significantly inhibits MARK4 activity (IC
= 6.204 µM). The evaluation of enthalpy change (∆H) and entropy change (∆S) suggested that the MARK4-RA complex formation is driven by hydrogen bonding and thus complexation process is seemingly specific. The consequence of MARK4 inhibition by RA was further evaluated by cell-based tau-phosphorylation studies, which suggested that RA inhibited the phosphorylation of tau. The treatment of cancer cells with RA significantly controls cell growth and subsequently induces apoptosis. Our study provides a rationale for the therapeutic evaluation of RA and RA-based inhibitors in MARK4 associated cancers and other diseases.
Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that works under acute transcriptional control by several stimuli, including serum and glucocorticoids. It plays a ...significant role in the cancer progression and metastasis, as it regulates inflammation, apoptosis, hormone release, neuro-excitability, and cell proliferation. SGK1 has recently been considered as a potential drug target for cancer, diabetes, and neurodegenerative diseases. In the present study, we have performed structure-based virtual high-throughput screening of natural compounds from the ZINC database to find potential inhibitors of SGK1. Initially, hits were selected based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and other drug-like properties. Afterwards, PAINS filter, binding affinities estimation, and interaction analysis were performed to find safe and effective hits. We found four compounds bearing appreciable binding affinity and specificity towards the binding pocket of SGK1. The docking results were complemented by all-atom molecular dynamics simulation for 100 ns, followed by MM/PBSA, and principal component analysis to investigate the conformational changes, stability, and interaction mechanism of SGK1 in-complex with the selected compound ZINC00319000. Molecular dynamics simulation results suggested that the binding of ZINC00319000 stabilizes the SGK1 structure, and it leads to fewer conformational changes. In conclusion, the identified compound ZINC00319000 might be further exploited as a scaffold to develop promising inhibitors of SGK1 for the therapeutic management of associated diseases, including cancer.
A sedentary lifestyle or lack of physical activity increases the risk of different diseases, including obesity, diabetes, heart diseases, certain types of cancers, and some neurological diseases. ...Physical exercise helps improve quality of life and reduces the risk of many diseases. Irisin, a hormone induced by exercise, is a fragmented product of FNDC5 (a cell membrane protein) and acts as a linkage between muscles and other tissues. Over the past decade, it has become clear that irisin is a molecular mimic of exercise and shows various beneficial effects, such as browning of adipocytes, modulation of metabolic processes, regulation of bone metabolism, and functioning of the nervous system. Irisin has a role in carcinogenesis; numerous studies have shown its impact on migration, invasion, and proliferation of cancer cells. The receptor of irisin is not completely known; however, in some tissues it probably acts via a specific class of integrin receptors. Here, we review research from the past decade that has identified irisin as a potential therapeutic agent in the prevention or treatment of various metabolic-related and other diseases. This article delineates structural and biochemical aspects of irisin and provides an insight into the role of irisin in different pathological conditions.
Cyclin-Dependent Kinase 6 (CDK6) plays an important role in cancer progression, and thus, it is considered as an attractive drug target in anticancer therapeutics. This study presents an evaluation ...of dietary phytochemicals, capsaicin, tocopherol, rosmarinic acid, ursolic acid, ellagic acid (EA), limonene, caffeic acid, and ferulic acid for their potential to inhibit the activity of CDK6. Molecular docking and fluorescence binding studies revealed appreciable binding affinities of these compounds to the CDK6. Among them, EA shows the highest binding affinity for CDK6, and thus a molecular dynamics simulation study of 200 ns was performed to get deeper insights into the binding mechanism and stability of the CDK6-EA complex. Fluorescence binding studies revealed that EA binds to the CDK6 with a binding constant of
= 10
M
and subsequently inhibits its enzyme activity with an IC
value of 3.053 µM. Analysis of thermodynamic parameters of CDK6-EA complex formation suggested a hydrophobic interaction driven process. The treatment of EA decreases the colonization of cancer cells and induces apoptosis. Moreover, the expression of CDK6 has been downregulated in EA-treated human breast cancer cell lines. In conclusion, this study establishes EA as a potent CDK6 inhibitor that can be further evaluated in CDK6 directed anticancer therapies.
The subject of this paper is the influence of chat marketing on customer support satisfaction. The purpose of the study is to determine the relationship between the use of chat marketing and customer ...support satisfaction, as well as to identify the essential factors that contribute to this relationship. Furthermore, this paper aims to provide theoretical insights into the influence of chat marketing on customer support satisfaction in financial startups. Many companies struggle to achieve the most efficient chat session and are uncertain about the best strategies, factors and types of chat to implement. Therefore, these findings will help financial startups to theoretically understand the aspects of chat marketing and customer support satisfaction. The object of this article is the impact of chat marketing on customer satisfaction, and the purpose is to reveal theoretical knowledge that will help identify the factors that contribute to chat marketing and customer satisfaction in financial startups. This paper discusses the importance of customer support for financial startups and the different approaches to providing customer support through emotional means. In addition, this paper highlights the importance of customer satisfaction through trust and commitment to build a positive relationship with the customer. Furthermore, this paper demonstrated the framework behind chat marketing, which includes the use of different tools such as live chat platforms, chatbots and live agents or human representatives that help to achieve customer satisfaction through customer support. Moreover, using methods such as: observation, survey and regression analysis, this paper has demonstrated the importance of customer centricity in the financial sector to provide key essentials for employees as incentives that maintain customer satisfaction, while ensuring the flexibility of real-time communication with chatbots or live agents, with the need to have the ease of use and flexibility and various other factors to contribute to customer support satisfaction. As a result, the paper emphasises that in order to increase customer satisfaction with financial start-ups, it is crucial to maintain a low response rate by providing fast and reliable customer assistance. Developing and regularly updating chatbots to facilitate smooth transitions to live agents in complex situations is essential. Implementing an effective ticketing system to automate and monitor issue resolution is essential, with a focus on resolving issues during chat interactions whenever possible. Adopting a hybrid strategy that combines live agents and chatbots helps to meet diverse customer needs in a timely manner. Investing in comprehensive training for live agents is necessary to ensure professional and timely service. In addition, continuous monitoring and analysis of customer feedback plays a key role in improving overall business performance.
Histone deacetylase 3 (HDAC3) is a member of the histone deacetylase family that has emerged as a crucial target in the quest for novel therapeutic interventions against various complex diseases, ...including cancer. The repositioning of FDA-approved drugs presents a promising avenue for the rapid discovery of potential HDAC3 inhibitors. In this study, we performed a structure-based virtual screening of FDA-approved drugs obtained from DrugBank. Candidate hits were selected based on their binding affinities and interactions with HDAC3. These promising hits were then subjected to a comprehensive assessment of their biological properties and drug profiles. Our investigation identified two FDA-approved drugs, Imatinib and Carpipramine, characterized by their exceptional affinity and specificity for the binding pocket of HDAC3. These molecules demonstrated a strong preference for HDAC3 binding site and formed interactions with functionally significant residues within the active site pocket. To gain deeper insights into the binding dynamics, structural stability, and interaction mechanisms, we performed molecular dynamics (MD) simulations spanning 300 nanoseconds (ns). The results of MD simulations indicated that Imatinib and Carpipramine stabilized the structure of HDAC3 and induced fewer conformational changes. Taken together, the findings from this study suggest that Imatinib and Carpipramine may offer significant therapeutic potential for treating complex diseases, especially cancer.
Context
In the pursuit of novel therapeutic possibilities, repurposing existing drugs has gained prominence as an efficient strategy. The findings from our study highlight the potential of repurposed ...drugs as promising candidates against receptor for advanced glycation endproducts (RAGE) that offer therapeutic implications in cancer, neurodegenerative conditions and metabolic syndromes. Through careful analyses of binding affinities and interaction patterns, we identified a few promising candidates, ultimately focusing on sertindole and temoporfin. These candidates exhibited exceptional binding affinities, efficacy, and specificity within the RAGE binding pocket. Notably, they displayed a pronounced propensity to interact with the active site of RAGE. Our investigation further revealed that sertindole and temoporfin possess desirable pharmacological properties that highlighted them as attractive candidates for targeted drug development. Overall, our integrated computational approach provides a comprehensive understanding of the interactions between repurposed drugs, sertindole and temoporfin and RAGE that pave the way for future experimental validation and drug development endeavors.
Methods
We present an integrated approach utilizing molecular docking and extensive molecular dynamics (MD) simulations to evaluate the potential of FDA-approved drugs, sourced from DrugBank, against RAGE. To gain deeper insights into the binding mechanisms of the elucidated candidate repurposed drugs, sertindole and temoporfin with RAGE, we conducted extensive all-atom MD simulations, spanning 500 nanoseconds (ns). These simulations elucidated the conformational dynamics and stability of the RAGE-sertindole and RAGE-temoporfin complexes.
Irisin is a clinically significant protein playing a valuable role in regulating various diseases. Irisin attenuates synaptic and memory dysfunction, highlighting its importance in Alzheimer's ...disease. On the other hand, Microtubule Affinity Regulating Kinase 4 (MARK4) is associated with various cancer types, uncontrolled neuronal migrations, and disrupted microtubule dynamics. In addition, MARK4 has been explored as a potential drug target for cancer and Alzheimer's disease therapy. Here, we studied the binding and subsequent inhibition of MARK4 by irisin. Irisin binds to MARK4 with an admirable affinity (
= 0.8 × 10
M
), subsequently inhibiting its activity (IC
= 2.71 µm). In vitro studies were further validated by docking and simulations. Molecular docking revealed several hydrogen bonds between irisin and MARK4, including critical residues, Lys38, Val40, and Ser134. Furthermore, the molecular dynamic simulation showed that the binding of irisin resulted in enhanced stability of MARK4. This study provides a rationale to use irisin as a therapeutic agent to treat MARK4-associated diseases.
The prevalence of Alzheimer's disease (AD) has been a major health concern for a long time. Despite recent progress, there is still a strong need to develop effective disease-modifying therapies. ...Several drugs have already been approved to retard the progression of AD-related symptoms; however, there is a need to develop an effective carrier system for the delivery of drugs to combat such diseases. In recent years, various biological macromolecules, including proteins, have been used as carriers for drug delivery. Irisin is a beneficial hormone in such diseases, including AD and related pathologies. Herein, the interaction mechanism of irisin with AD drugs such as memantine, galantamine, and fluoxetine is investigated. Fluorescence studies revealed that the above drugs bind to irisin with significant affinity, with fluoxetine having the highest binding affinity. Isothermal titration calorimetry (ITC) complemented the spontaneous binding of these drugs with irisin, delineating various associated thermodynamic and binding parameters. Molecular docking further validated the fluorescence and ITC results and unfolded the mechanism that hydrogen bonding governs the binding of fluoxetine to irisin with a significant binding score, i.e., -6.3 kcal/mol. We believe that these findings provide a promising solution to fight against AD as well as a platform for further research to utilize irisin in the drug-delivery system for an effective therapeutic strategy.
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