Unrevealing the multitargeted potency of 3-1-BCMIYPPA against lung cancer structural maintenance and suppression proteins through pharmacokinetics, QM-DFT, and multiscale MD simulation studies.

Lung cancer, a relentless and challenging disease, demands unwavering attention in drug design research. Single-target drugs have yielded limited success, unable to effectively address this malignancy's profound heterogeneity and often developed resistance. Consequently, the clarion call for lung cancer drug design echoes louder than ever, and multitargeted drug design emerges as an imperative approach in this landscape, which is done by concurrently targeting multiple proteins and pathways and offering a beacon of hope. This study is focused on the multitargeted drug designing approach by identifying drug candidates against human cyclin-dependent kinase-2, SRC-2 domains of C-ABL, epidermal growth factor and receptor extracellular domains, and insulin-like growth factor-1 receptor kinase. We performed the multitargeted molecular docking studies of Drug Bank compounds using HTVS, SP and XP algorithms and poses filter with MM\GBSA against all proteins and identified DB02504, namely [3-(1-Benzyl-3-Carbamoylmethyl-2-Methyl-1h-Indol-5-Yloxy)-Propyl-]-Phosphonic Acid (3-1-BCMIYPPA) as multitargeted lead with docking and MM\GBSA score range from -8.242 to -6.274 and -28.2 and -44.29 Kcal/mol, respectively. Further, the QikProp-based pharmacokinetic computations and QM-based DFT showed acceptance results against standard values, and interaction fingerprinting reveals that THR, MET, GLY, VAL, LEU, GLU and ASP were among the most interacting residues. The NPT ensemble-based 100ns MD simulation in a neutralised state with an SPC water model has also shown a stable performance and produced deviation and fluctuations <2Å with huge interactions, making it a promising multitargeted drug candidate-however, experimental studies are suggested.

Homozygous Missense Variant in the N-Terminal Region of ANK3 Gene Is Associated with Developmental Delay, Seizures, Speech Abnormality, and Aggressive Behavior.

Introduction: Intellectual disability (ID) is a lifelong disability that affects an individual‧s learning capacity and adaptive behavior. Such individuals depend on their families for day-to-day survival and pose a significant challenge to the healthcare system, especially in developing countries. ID is a heterogeneous condition, and genetic studies are essential to unravel the underlying cellular pathway for brain development and functioning. Methods: Here we studied a female index patient, born to a consanguineous Pakistani couple, showing clinical symptoms of ID, ataxia, hypotonia, developmental delay, seizures, speech abnormality, and aggressive behavior. Whole exome sequencing (WES) coupled with Sanger sequencing was performed for molecular diagnosis. Further, 3D protein modeling was performed to see the effect of variant on protein structure. Results: WES identified a novel homozygous missense variant (c.178T>C; p.Tyr60His) in the ANK3 gene. In silico analysis and 3-dimensional (3D) protein modeling supports the deleterious impact of this variant on the encoding protein, which compromises the protein‧s overall structure and function. Conclusion: Our finding supports the clinical and genetic diversity of the ANK3 gene as a plausible candidate gene for ID syndrome. Intelligence is a complex polygenic human trait, and understanding molecular and biological pathways involved in learning and memory can solve the complex puzzle of how cognition develops. Intellectual disability (ID) is defined as a deficit in an individual‧s learning and adaptive behavior at an early age of onset [American Psychiatric Association, 2013]. It is one of the major medical, and cognitive disorders with a prevalence of 1-3% in the population worldwide [Leonard and Wen, 2002]. ID often exists with other disabling mental conditions such as autism, attention deficit hyperactivity disorder, epilepsy, schizophrenia, bipolar disorder, or depression. Almost half of the cases appear to have a genetic explanation that ranges from cytogenetically visible abnormalities to monogenic defects [Flint, 2001; Ropers, 2010; Tucker-Drob et al., 2013]. Intellectual disability is a genetically heterogeneous condition, and more than 700 genes have been identified to cause ID alone or as a part of the syndrome. Research in X-linked ID has identified more than 100 disease-causing genes on the X chromosome that play a role in cognition; however, research into autosomal causes of ID is still ongoing [Vissers et al., 2016].

Patients' satisfaction with nursing care quality and associated factors: A cross-section study.

AIM: This research aimed to evaluate patients' satisfaction with the nursing care quality during their hospitalization. DESIGN: Quantitative cross-sectional descriptive design. METHODS: A convenience sample of 238 patients were recruited from hospitals in two provinces in Saudi Arabia. Patient satisfaction was measured by the Arabic version of the Patients' Satisfaction with Nursing Care Quality Questionnaire (PSNCQQ-Ar). RESULTS: Significant differences were found between Saudi provinces regarding the overall quality of nursing care (M = 4.65, p < 0.001). The study revealed mean significant variations between patient satisfaction with nursing care and sociodemographic factors, including age (p = 0.002), education level (p = 0.047), marital status (p = 0.017), employment status (p = 0.038), urban vs. suburban residence (p = 0.006), length of hospitalization (p = 0.001), and accompaniment by a family member (p = 0.014). Improving patients' experience during their hospitalization requires regular examination of the quality of nursing care services. PATIENT CONTRIBUTION: This research enhances our understanding of patients satisfaction toward the quality of nursing care received during hospitalization.

Unveiling the multitargeted potential of N-(4-Aminobutanoyl)-S-(4-methoxybenzyl)-L-cysteinylglycine (NSL-CG) against SARS CoV-2: a virtual screening and molecular dynamics simulation study.

The coronaviridae family has caused the most destruction among all the viral families in modern sciences. It is one of the recently discovered and added members of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has caused the global pandemic and significant destruction worldwide. However, scientists worldwide have developed vaccines, which are being given to humans. The mutated strain of the virus has caused various uncertainties about whether the discovered drug and vaccines affect it. Even after the World Health Organization's approval for the vaccines, their effectiveness and protection ratio are still a major concern. At the community level, to this date, there is no medicine available to cure the patients. In this study, we have screened the vast library from Drug Bank and identified N-(4-Aminobutanoyl)-S-(4-methoxybenzyl)-L-cysteinylglycine (NSL-CG) that can work against two major targets of SARS CoV-2, replication-transcription and RNA dependent polymerase. Further, we have performed the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and molecular dynamics simulation of the compound with both proteins individually, giving us enough evidence that the said drugs can work against the two targets together. Inhibiting the action of any of both proteins may lead to retaining the virus, and having a dual-targeted drug can be an extra precise measure for this process. The NSL-CG is an experimental drug belonging to the peptidomimetics class included in the small group of drugs with a docking score of -9.079 kcal/mol with replication-transcription -7.885 kcal/mol with RNA-dependent polymerase. Hence, through the complete flowed study, the NSL-CG can be further experimentally validated in in-vitro and in-vivo conditions before human utilisation.Communicated by Ramaswamy H. Sarma.

Identification of compelling inhibitors of human norovirus 3CL protease to combat gastroenteritis: A structure-based virtual screening and molecular dynamics study.

Human noroviruses (NV) are the most prevalent cause of sporadic and pandemic acute gastroenteritis. NV infections cause substantial morbidity and death globally, especially amongst the aged, immunocompromised individuals, and children. There are presently no authorized NV vaccines, small-molecule therapies, or prophylactics for humans. NV 3 C L protease (3CLP) has been identified as a promising therapeutic target for anti-NV drug development. Herein, we employed a structure-based virtual screening method to screen a library of 700 antiviral compounds against the active site residues of 3CLP. We report three compounds, Sorafenib, YM201636, and LDC4297, that were revealed to have a higher binding energy (BE) value with 3CLP than the control (Dipeptidyl inhibitor 7) following a sequential screening, in-depth molecular docking and visualization, physicochemical and pharmacological property analysis, and molecular dynamics (MD) study. Sorafenib, YM201636, and LDC4297 had BEs of -11.67, -10.34, and -9.78 kcal/mol with 3CLP, respectively, while control had a BE of -6.38 kcal/mol. Furthermore, MD simulations of the two best compounds and control were used to further optimize the interactions, and a 100 ns MD simulation revealed that they form stable complexes with 3CLP. The estimated physicochemical, drug-like, and ADMET properties of these hits suggest that they might be employed as 3CLP inhibitors in the management of gastroenteritis. However, wet lab tests are a prerequisite to optimize them as NV 3CLP inhibitors.

Factors influencing hospital anxiety and depression among emergency department nurses during the COVID-19 pandemic: A multi-center cross-sectional study.

Introduction: The emergency department (ED) is a highly stressful environment, which exposes nurses to infection. ED nurses handle life-threatening conditions, endure long working hours, and deal with anxious patients and their families. Aim: This study aimed to examine factors, which may influence anxiety and depression levels among ED nurses during the coronavirus disease 2019 (COVID-19) pandemic. Methods: A cross-sectional design was used with 251 participants from six hospitals in Saudi Arabia (mean age = 32.7 ± 6.59, range = 21-54 years, 70.5% females). Data were collected using the Hospital Anxiety and Depression Scale (HADS), and the analysis was conducted using structural equation modeling (SEM). Results: Based on the HADS scores, 29.1 and 25.5% of ED nurses were identified as doubtful cases for depression and anxiety, respectively. Additionally, 34.7 and 43.3% of ED nurses were identified as definite cases for depression and anxiety, respectively. Higher anxiety levels were observed among female nurses, nurses with lower physical activity levels, and nurses who worked in urban areas. Low physical activity levels and more than 6 years of work experience correlated with a higher level of depression. None of the hypothesized paths in the anxiety and depression models were significant, except for two observed variables-namely, work location and physical exercise in the anxiety model and physical exercise in the depression model. Conclusion: Emergency department nurses expressed high levels of anxiety and depression during the COVID-19 pandemic, which may negatively affect their performance and reduce care quality. Therefore, health care leaders should implement specialized mental health education programs focused on nursing occupational safety and support to improve ED nurses' psychological well-being. Specific attention should be paid to ED female nurses who work in urban areas, especially those with more than 6 years of experience.

In-Silico Screening and Molecular Dynamics Simulation of Drug Bank Experimental Compounds against SARS-CoV-2.

For the last few years, the world has been going through a difficult time, and the reason behind this is severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), one of the significant members of the Coronaviridae family. The major research groups have shifted their focus towards finding a vaccine and drugs against SARS-CoV-2 to reduce the infection rate and save the life of human beings. Even the WHO has permitted using certain vaccines for an emergency attempt to cut the infection curve down. However, the virus has a great sense of mutation, and the vaccine's effectiveness remains questionable. No natural medicine is available at the community level to cure the patients for now. In this study, we have screened the vast library of experimental drugs of Drug Bank with Schrodinger's maestro by using three algorithms: high-throughput virtual screening (HTVS), standard precision, and extra precise docking followed by Molecular Mechanics/Generalized Born Surface Area (MMGBSA). We have identified 3-(7-diaminomethyl-naphthalen-2-YL)-propionic acid ethyl ester and Thymidine-5'-thiophosphate as potent inhibitors against the SARS-CoV-2, and both drugs performed impeccably and showed stability during the 100 ns molecular dynamics simulation. Both of the drugs are among the category of small molecules and have an acceptable range of ADME properties. They can be used after their validation in in-vitro and in-vivo conditions.

Glycine Betaine Relieves Lead-Induced Hepatic and Renal Toxicity in Albino Rats.

Lead (Pb) is a widespread and nondegradable environmental pollutant and affects several organs through oxidative mechanisms. This study was conducted to investigate the antioxidant protective effect of glycine betaine (GB) against Pb-induced renal and hepatic injury. Male albino rats (n = 45) were divided into three groups: G1 untreated control, G2 Pb-acetate (50 mg/kg/day), and G3 Pb-acetate (50 mg/kg/day) plus GB (250 mg/kg/day) administered for 6 weeks. For G3, Pb-acetate was administered first and followed by GB at least 4 h after. Pb-acetate treatment (G2) resulted in a significant decrease in renal function, including elevated creatinine and urea levels by 17.4% and 23.7%, respectively, and nonsignificant changes in serum uric acid levels. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphates (ALP) activities were significantly increased with Pb treatment by 37.6%, 59.3%, and 55.1%, respectively. Lipid peroxidation level was significantly increased by 7.8 times after 6 weeks of Pb-acetate treatment. The level of reduced glutathione (GSH-R) significantly declined after Pb-acetate treatment. Pb-acetate treatment also reduced the activities of superoxide dismutase (SOD), glutathione-S-transferase (GST), and glutathione peroxidase (GSH-PX) by 74.1%, 85.0%, and 40.8%, respectively. Treatment of Pb-intoxicated rats with GB resulted in a significant reduction in creatinine, urea, ALT, AST, and lipid peroxidation, as well as a significant increase in the level of GSH-R and in the activities of ALP, SOD, GST, and GSH-PX. The molecular interaction between GB and GSH-PX indicated that the activation of GSH-PX in Pb-intoxicated rats was not the result of GB binding to the catalytic site of GSH-PX. The affinity of GB to bind to the catalytic site of GSH-PX is lower than that of H2O2. Thus, GB significantly mitigates Pb-induced renal and liver injury through the activation of antioxidant enzymes and the prevention of Pb-induced oxidative damage in the kidney and liver.

Hemi-Babim and Fenoterol as Potential Inhibitors of MPro and Papain-like Protease against SARS-CoV-2: An In-Silico Study.

The coronaviruses belong to the Coronaviridae family, and one such member, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is causing significant destruction around the world in the form of a global pandemic. Although vaccines have been developed, their effectiveness and level of protection is still a major concern, even after emergency approval from the World Health Organisation (WHO). At the community level, no natural medicine is currently available as a cure. In this study, we screened the vast library from Drug Bank and identified Hemi-Babim and Fenoterol as agents that can work against SARS-CoV-2. Furthermore, we performed molecular dynamics (MD) simulation for both compounds with their respective proteins, providing evidence that the said drugs can work against the MPro and papain-like protease, which are the main drug targets. Inhibiting the action of these targets may lead to retaining the virus. Fenoterol is a beta-2 adrenergic agonist used for the symptomatic treatment of asthma as a bronchodilator and tocolytic. In this study, Hemi-Babim and Fenoterol showed good docking scores of -7.09 and -7.14, respectively, and performed well in molecular dynamics simulation studies. Re-purposing the above medications has huge potential, as their effects are already well-proven and under public utilisation for asthma-related problems. Hence, after the comprehensive pipeline of molecular docking, MMGBSA, and MD simulation studies, these drugs can be tested in-vivo for further human utilisation.

A Therapeutic Journey of Pyridine-based Heterocyclic Compounds as Potent Anticancer Agents: A Review (From 2017 to 2021).

Pyridine derivatives are the most common and significant heterocyclic compounds, which show their fundamental characteristics to various pharmaceutical agents and natural products. Pyridine derivatives possess several pharmacological properties and a broad degree of structural diversity that is most valuable for exploring novel therapeutic agents. These compounds have an extensive range of biological activities such as antifungal, antibacterial, anticancer, anti-obesity, anti-inflammatory, antitubercular, antihypertensive, antineuropathic, antihistaminic, antiviral activities, and antiparasitic. The potent therapeutic properties of pyridine derivatives allow medicinal chemists to synthesize novel and effective chemotherapeutic agents. Consequently, the imperative objective of this comprehensive review is to summarize and investigate the literature regarding recent advancements in pyridine-based heterocycles to treat several kinds of cancer. Furthermore, the performances of pyridine derivatives were compared with some standard drugs, including etoposide, sorafenib, cisplatin, and triclosan, against different cancer cell lines. We hope this study will support the new thoughts to pursue the most active and less toxic rational designs.

Effect of pre-swelling and freezing/thawing cycles on the structure of molecular, morphological, and functional properties of potato starch.

This study aimed to investigate the effect of pre-swelling at 55°C for 1 hr followed by freezing-thawing cycles (PFTCs), and freezing-thawing cycles (FTCs) in the starch granules to improve the freeze-thaw stability and evaluate its impact on the molecular, morphological, and functional properties of potato starch (PS). FTCs at 1 cycle and 7 cycles were applied for both treated PS. Microscopical structure, thermal, molecular, and functional properties (i.e., swelling power, solubility, shear viscosity, and gel strength) were comprehensively analyzed. In terms of granule structures, treated PS by FTC showed a slightly affected on the surface of starch granules, while treating PS by PFTC showed an affected in the form of small cracks and holes in the outer surface of starch granules. The gelatinization enthalpy (∆Hgel ) values decreased in the treated PS compared with the native. Thus, decreasing was systemically increased with the number of applied cycles from 1- to 7-cycle. The viscosity of treated PS decreased systematically with molecular degradation or the physical modification, with remarkable reduction, particularly at a higher shear rate (150°C). Treated PS by FTC showed a clear difference (p ≤ .05) in gel values compared with the native at disintegration temperature 115°C. Finally, the degradation of the molecular properties showed significant differences between the native and treated PS either by the FTC or PFTC in molecular weight of starch and amylose without debranching and after debranching by pullulanase enzyme. PRACTICAL APPLICATIONS: Freezing is one of the standard preservation methods used for ready-to-eat products. When this type of food's exposed to more freeze-thaw cycles, the phase separation will be increased due to the increase in retrogradation of amylopectin. To avoid such changes during frozen storage, native potato starch (PS) was modified using both pre-swelling followed by freezing-thawing cycles (PFTCs) and freezing-thawing cycles (FTCs) at 1- and 7-cycle to enhance starch properties, such as swelling power, solubility, shear viscosity, and gel strength. The findings of this study might add to the theoretical understanding of modified PS and act as a guideline for modified starch manufacturing.

Cell and nanoparticle transport in tumour microvasculature: the role of size, shape and surface functionality of nanoparticles.

Through nanomedicine, game-changing methods are emerging to deliver drug molecules directly to diseased areas. One of the most promising of these is the targeted delivery of drugs and imaging agents via drug carrier-based platforms. Such drug delivery systems can now be synthesized from a wide range of different materials, made in a number of different shapes, and coated with an array of different organic molecules, including ligands. If optimized, these systems can enhance the efficacy and specificity of delivery compared with those of non-targeted systems. Emerging integrated multiscale experiments, models and simulations have opened the door for endless medical applications. Current bottlenecks in design of the drug-carrying particles are the lack of knowledge about the dispersion of these particles in the microvasculature and of their subsequent internalization by diseased cells (Bao et al. 2014 J. R. Soc. Interface 11, 20140301 (doi:10.1098/rsif.2014.0301)). We describe multiscale modelling techniques that study how drug carriers disperse within the microvasculature. The immersed molecular finite-element method is adopted to simulate whole blood including blood plasma, red blood cells and nanoparticles. With a novel dissipative particle dynamics method, the beginning stages of receptor-driven endocytosis of nanoparticles can be understood in detail. Using this multiscale modelling method, we elucidate how the size, shape and surface functionality of nanoparticles will affect their dispersion in the microvasculature and subsequent internalization by targeted cells.