Molecular docking and ADMET studies of halogenated metabolites from marine sponges as inhibitors of wild-type and mutants PBP2 in Neisseria gonorrhoeae.

Gonorrhoea is a sexually transmitted infection (STI) caused by the bacteria Neisseria gonorrhoeae. Gonorrhoea symptoms can vary, although roughly 50% of women and 10% of men infected with N. gonorrhoeae may be asymptomatic. If left untreated, gonorrhoea can cause major health problems. However, no effective treatment or vaccination is currently available. The enzyme penicillin-binding protein 2 (PBP2) is necessary for cell wall synthesis during N. gonorrhoeae cell growth. The goal of this study is to investigate the molecular interactions of three PBP2 variants with halogenated marine sponge metabolites using molecular docking, molecular dynamic simulation, and ADMET analysis. The docking findings were evaluated using the glide gscore, and the top 20 compounds docked against each PBP2 protein receptor were chosen. Furthermore, the selected compounds underwent ADMET analysis, indicating that they have the potential for therapeutic development. Among the selected compounds, Bromoageliferin had the highest affinity for PBP2, Psammaplysin E for the penicillin-resistant variation of PBP2 protein, and Preaxinellamine for the cephalosporin-resistant variant of PBP2 protein. Additionally, MM-GBSA binding free energy and molecular dynamics simulations were used to support the docking investigations. The results of the study suggest that these compounds may eventually be used to treat gonorrhoea. However, computer validations were included in this study, and more in-vitro research is required to turn these prospective inhibitors into clinical drugs.Communicated by Ramaswamy H. Sarma.

The Impact of Androgenic Alopecia on the Quality of Life of Male Individuals: A Cross-Sectional Study.

Background Hair plays a significant role in physical appearance and hair loss can profoundly affect self-esteem and mental health. Studies show that people with clinically obvious and undetectable hair loss may have dramatically decreased quality of life (QoL). This study investigated the impact of androgenic alopecia on the quality of life of male individuals in the Eastern Province of Saudi Arabia and their willingness to seek treatment. Methods In the eastern province of Saudi Arabia, a cross-sectional study was carried out among men identified with androgenic alopecia (AGA). A self-administered survey was disseminated among the patients through social media sites. The questionnaire includes fundamental demographic factors including age, place of residence, level of education, the severity of androgenic alopecia, treatment method, and Skindex-29 to assess the patient's quality of life. Results Four hundred-two male patients out of 717 participants were selected, and 158 (39.3%) were aged between 20 to 29 years old. Satisfaction with treatment medication was reported by 24 (19.5%) out of those who underwent treatment (n=123). Less effectiveness was the most common reason for treatment dissatisfaction (81, 81.8%). The overall mean Skindex-29 score was 23.2 (SD 19.6) out of 100 points. Younger age, suffering hair loss for a shorter duration, undergoing alopecia treatment, being diagnosed with alopecia by a medical doctor, and having a moderate level of AGA were the factors that greatly affected the patient's QoL. Conclusion Consistent with the literature, this study showed that AGA significantly impaired patients' QoL. Among QoL domains, the symptoms domain had a greater effect on patients than the emotions or functional domains. Younger males who were suffering recently from hair loss and were diagnosed with AGA by the medical doctor demonstrated greater QoL impairment than the rest of the patients. A multicenter study may result in a better representation of the impact of QoL in patients with AGA.

Prediction of the 10-Year Risk of Cardiovascular Diseases Among Patients in Primary Health Care Centers in Eastern Province, Saudi Arabia.

Background Cardiovascular diseases (CVDs), primarily coronary artery disease (CAD) and stroke, stand as a leading cause of morbidity and mortality globally. Our objective was to predict the 10-year risk of CVD in the Eastern Province of Saudi Arabia. Methods This cross-sectional study was conducted in eight randomly selected primary healthcare centers using cluster sampling based on geographical location in Saudi Arabia's Eastern Province, specifically the Al-Ahsa region. The study aimed to assess the risk of developing CVD in the next 10 years among patients with at least one cardiovascular risk factor. Patients visiting the healthcare centers for checkups filled out the Framingham Cardiovascular Disease (10-year risk) score questionnaire. Results Of the 665 patients enrolled, 54.4% were female. The average age of the patients was 54.2 (SD 8.48) years. The overall average Framingham Risk Score (FRS) percentage was 19.2% (SD 15.4%). In terms of 10-year CVD risk, 34.6% of the patients were at high risk, 31.6% were at moderate risk, and 33.8% were considered low-risk individuals. Factors associated with a higher risk of CVD included older age, male gender, lower educational attainment, smoking, normal BMI, stage 2 hypertension, and diagnoses of hypertension, diabetes, and obesity. Conclusion Utilizing the FRS, it was determined that older men with lower educational levels had a higher 10-year risk of developing CVD. Furthermore, CVD risk factors such as diabetes, hypertension, obesity, and smoking were associated with individuals' CVD risk. Considering the ease of use and applicability of the FRS in daily clinical practice, as well as its potential to identify high-risk individuals, a more systematic implementation in general practice appears to be warranted.

The determinants of smart government systems adoption by public sector organizations in Saudi Arabia.

This study investigates the determinants of smart government systems that are used in public service organizations in Saudi Arabia. The world's developed nations have conducted studies on smart government systems, but little research has been done on the Middle East, particularly in Saudi Arabia. This study fills the lacuna in the literature. Based on a number of theories including the Technology, Organization, and Environment framework (TOE), Unified Theory of Acceptance and Use of Technology (UTAUT), and Technology Acceptance Models (TAM), the study established an integrated conceptual research model. Online survey questionnaires were sent to 2060 employees in four ministries and after the second reminder a total of 427 completed answers were received, of which 419 (22% response rate) were deemed useable for the analysis. Multivariate statistical analysis was used to analyze the data and results indicated that 51% of the variance (R2 = 0.51) of employees' perceptions of smart government systems is explained by independent determinants. Findings show that security concerns (t (419) = 2.051, p < 0.041), ICT strategy (t (419) = 4.215, p < 0.000), managerial support (t (419) = 5.027, p < 0.000), incentives (t (419) = 5.263, p < 0.000), and trust (t (419) = -1.957, p < 0.050) are significant predictors of smart government systems acceptance. Meanwhile cultural values (t (419) = 0.669, p < 0.504) and religious values (t (419) = 1.082, p < 0.280) have no significant effect on the attitude to smart system adoption. Perception was found to have a strong significant effect on adoption of smart government systems (t (419) = 8.411, p < 0.000). These results have significant implications for the Saudi government's drive to implement smart government systems in all its agencies.

Non-medial Subperiosteal Abscess in a 63-Year-Old Female: A Case Report and Literature Review.

We present a rare case of non-medial subperiosteal abscess secondary to orbital cellulitis in a 63-year-old female. The patient reported a five-day history of progressive swelling, pain, and diminished vision in the left eye. Computed tomography (CT) of the orbit revealed an extraconal soft tissue density, suggestive of an orbital collection, which when correlated clinically and radiologically, was diagnosed as orbital cellulitis secondary to sinusitis, leading to a subperiosteal abscess. Despite undergoing multiple external drainage procedures, the patient, unfortunately, experienced complete vision loss in the affected eye. While non-medial abscesses due to orbital cellulitis are infrequent, they are often associated with more severe outcomes, including vision loss and intracranial complications, compared to those in medial locations. This case underscores the importance of combined surgical approaches, including both sinus and external drainage, to prevent severe vision loss and potentially life-threatening intracranial sequelae.

Inhibition of hepatitis B virus activities by Rhazya stricta­derived acacetin and acetyl­ß­carboline.

Hepatitis B virus (HBV) causes acute and chronic liver diseases, leading to cirrhosis and hepatocellular carcinoma. Although direct-acting nucleoside analogs, such as lamivudine (LAM), adefovir and famciclovir, are available, emergence of drug-resistance due to mutations in HBV polymerase (POL) restricts their further use. Alternatively, numerous plant products and compounds isolated from plants have been reported to confer anti-HBV efficacies without any sign of resistance in vitro or in vivo. As, flavonoids and alkaloids are the most widely reported antivirals, the anti-HBV activities of the flavonoid acacetin (ACT) and the alkaloid acetyl-ß-carboline (ABC) from the aerial parts of Rhazya stricta were assessed in the present study. Both compounds were isolated from the ethyl acetate fraction of the total methanol extract using column and thin-layer chromatography, and their structures were determined by nuclear magnetic resonance spectroscopy (NMR). Both compounds (at 6.25-50 µg/ml) showed a lack of hepatocytotoxicity in cultured HepG2.2.15 cells. Anti-HBV ELISA [hepatitis B surface antigen (HBsAg) and hepatitis B pre-core-antigen (HBeAg)] on HepG.2.2.15 cells following treatment with selected concentrations (12.5, 25 and 50 µg/ml) of both compounds showed dose- and time-dependent anti-HBV activities. Compared with those in the untreated control at day 5, ACT and ABC (25 µg/ml, each) maximally inhibited HBsAg synthesis by 43.4 and 48.7%, respectively, whilst also maximally inhibiting HBeAg synthesis by 41.2 and 44.2%, respectively, in HepG2.2.15 cells. Comparatively, quercetin and LAM (standards; POL inhibitors) suppressed HBsAg (63.9 and 60.2%, respectively) and HBeAg synthesis (87.1 and 84.3%, respectively) by larger magnitudes. Molecular docking of ACT and ABC structures performed in AutoDock revealed their hydrogen bonding with the drug-sensitive [wild-type (wt)-POL] 'Tyr-Met-Asp-Asp' motif, in addition to the drug-resistant [mutant (mut)-POL] 'Tyr-Ile-Asp-Asp' motif residues of the polymerase binding-pocket, along with other electrostatic interactions. In the wt-POL complex, both compounds showed good interactions with Asp205. In the mut-POL complex, ACT and ABC interacted with Tyr203-Asp205 and Tyr203-Ile204, respectively. In conclusion, to the best of our knowledge, the present study demonstrates anti-HBV efficacies of ACT and ABC in vitro for the first time, endorsed by in silico data. However, further molecular and pharmacological studies are required to validate their pre-clinical therapeutic potential.

Impact of Ramadan Fasting on the Severity of Symptoms Among a Cohort of Patients With Gastroesophageal Reflux Disease (GERD).

INTRODUCTION:  Gastroesophageal reflux disease (GERD) is a condition caused by the reflux of stomach contents into the esophagus. Heartburn, chest discomfort, and regurgitation are the main symptoms. Medications, surgical procedures, and lifestyle modification are considered treatment options. Fasting is believed to be one of the lifestyle modifications that helps minimize GERD symptoms. Muslims abstain from eating, drinking, and smoking from dawn until dusk. The objectives of our study were to investigate the relationship between fasting and GERD symptoms and evaluate how fasting affects GERD symptoms in Saudi Arabia. METHODOLOGY: This was a longitudinal study that selected GERD patients for its consecutive sampling. The patients answered the questionnaires at two separate times: once during Ramadan and once after Ramadan. A validated gastroesophageal reflux disease health-related quality of life (GERD-HRQL) self-administered survey was used. RESULT: After Ramadan, heartburn symptoms significantly decreased, particularly when lying down. Overall, the 45-point heartburn score decreased from 17.9 during Ramadan to 14.3 thereafter. The regurgitation score decreased from 12.3 during Ramadan to 9.9 after fasting, with statistical significance (P = .049). Although satisfaction was much higher after Ramadan (17% vs. 15.1%), there was no statistical significance (P = .422), and 45.3% of the patients were satisfied with their health state during Ramadan compared to 34% after Ramadan. There was no relationship between the severity of GERD symptoms before or after fasting and the type of food, the timing of eating, or the amount of food consumed. CONCLUSION: The results suggested that Ramadan fasting may improve GERD symptoms. However, more studies are required to validate these results and comprehend the underlying mechanisms.

Perception of Parents Towards COVID-19 Vaccine for Children in Saudi Population.

Background Coronavirus disease 2019 (COVID-19) is a contagious disease that is caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). With the rapid spread of this pandemic, vaccination has been a breakthrough solution. At the time of conducting the study, COVID-19 vaccines were only approved for adults 18 years and older. Therefore, the aim of the study was to assess the parents' likelihood of vaccinating their children once the recommendation for pediatric vaccination is established. Methods This was a cross-sectional study in which a self-administered survey was distributed to all parents visiting National Guard primary healthcare centers in Riyadh, Saudi Arabia. The questionnaires were distributed to parents attending primary care clinics. Data collected in the questionnaire include demographics (gender, marital status, educational level, and age), questions assessing parental perception towards the COVID-19 vaccine, and willingness to offer the vaccine to their children. Results A total of 333 respondents completed the survey with a response rate of 83.3%. Half of the participants were males and the other half were females with the majority (45.6%) aged between 31 and 40 years old. In terms of parental acceptability of vaccinating their children against COVID-19, 53.7% of the parents were willing to vaccinate their children as opposed to 27% who were reluctant to do so. Of those who refused, 97.5% and 96.6% cited lack of information and evidence, respectively, as the most common reasons for not accepting COVID-19 vaccine. We have found that age of the parents, especially those 31-40 years old, age of their children, especially 4-12 years old, and previous acceptance of the seasonal influenza vaccine were significantly associated with higher parental acceptability of COVID-19 vaccine. In contrast, gender, marital status and educational level were not statistically significant factors. Conclusion As COVID-19 spread globally and made people's lives in danger, vaccination became a highly important measure to halt the spread of the disease. Parents are now given the choice of protecting their beloved children from COVID-19 infection and its possible complications. Based on our findings, we noticed that majority of parents are going to vaccinate their children. In addition, some certain age groups of parents and children were significantly associated with decreased vaccine hesitancy to take the COVID-19 vaccine.

New terpenic and phenolic compounds from Suaeda monoica reverse oxidative and apoptotic damages in human endothelial cells.

Elevation in hyperglycemia-associated methylglyoxal level can trigger vascular endothelial cells oxidative stress and apoptosis. The present work assesses the cell proliferative, anti-oxidative and anti-apoptotic potential of Suaeda monoica derived four new terpenes: a norsesquaterpenol (normonisesquaterpenol), a monocyclic triterpenoid (suaedanortriterpene dione), an aromatic monoterpenic ester and a labdane-type norditerpenic xyloside as well as two new phenols: an alkylated ß-naphthol and a ß-methoxy naphthalene in cultured human umbilical vein endothelial cells (HUVEC). Of these, suaedanortriterpenedione (53.7%), normonisesquaterpenol (51.4%) and norditerpenic xyloside (48%) showed the most promising cell proliferative activities compared to others. Moreover, normonisesquaterpenol, norditerpenic xyloside and suaedanortriterpenedione efficiently reversed the oxidative and apoptotic cell damage via downregulation of capase-3/7 by 44.3%, 42.2% and 39.4%, respectively against dichlorofluorescin, whereas by 46.2%, 43.5% and 42.5%, respectively against methylglyoxal. Aminoguanidine, the reference drug inhibited caspase-3/7 activity by 56.2% and 54.7% through attenuation of dichlorofluorescin and methylglyoxal, respectively. Further in silico molecular docking analysis revealed formation of stable complexes between the tested compounds and caspase-3/7. Conclusively, we for the first time demonstrate the growth stimulatory, anti-oxidative and anti-apoptotic salutations of S. monoica derived novel compounds in human endothelial cells. This warrants their further assessment as vascular cell protective and rejuvenating therapeutics, especially in hyperglycemic conditions.

Burnout and Associated Risk Factors in Pediatric Residents.

Background: Burnout is a syndrome characterized by emotional exhaustion, depersonalization, and a low sense of personal accomplishment. The aim of this study was to identify burnout incidence in pediatric residents and evaluate possible risk factors for burnout. Methods: Using a cross-sectional study design, we approached all pediatric residents in the Saudi Pediatrics Residency Program in Riyadh, Saudi Arabia (n=457) between January and March 2019. The Maslach Burnout Inventory-Human Services Survey was used to assess burnout incidence. In addition, demographic factors, schedule burden, career choice satisfaction, and work-life balance were assessed. Results: The response rate was 57.8% (264/457). Males represented 46.6%. Only 14% of the residents in the study were satisfied with their work-life balance, and 62% were satisfied with their career choice of pediatrics. The overall high burnout incidence was 15.9%, the high emotional exhaustion incidence was 63.6%, the high depersonalization incidence was 27.7%, and the low sense of personal accomplishment incidence was 48.5%. In the multivariate analysis, an increase in the average number of on-calls per month (odds ratio [OR]=1.66, 95% CI 1.12-2.46; P=0.012) and satisfaction with salary (OR=0.47, 95% CI 0.33-0.66; P<0.001) showed significant associations with high overall burnout. Conclusion: We found a high level of emotional exhaustion and a low sense of personal accomplishment among respondents. However, less than one-third of residents had feelings of depersonalization or overall high burnout. Residency program directors may need to make modifications in their programs to ensure a good work-life balance for residents that will help ensure that these physicians provide safe and sustained patient care.

Musculoskeletal pain among male faculty members of the College of Medicine and College of Dentistry.

ABSTRACT: We aimed to establish the local prevalence of musculoskeletal pain among faculty members in Saudi Arabia and describe the patient's risk factors and preventive measures that may reduce its burden.An observational, quantitative, cross-sectional study was carried out to evaluate the prevalence of musculoskeletal pain and its risk factors among male faculty members in the College of Medicine and Dentistry, using a designed questionnaire based on the Standardized Nordic Musculoskeletal Questionnaire. Chi-square testing at a significance level of P < .05, was used for comparative analysis. SPSS version 26 was used for all analyses.Ninety responders participated in the survey analysis. The prevalence of musculoskeletal pain among faculty members was 77.8%, and the most common site of musculoskeletal pain occurred at two different sites of the three (low back, neck, and shoulder), with a prevalence of 38.9%. As for risk factors of musculoskeletal pain, only age group showed a significant correlation with the site of musculoskeletal pain (P = .024), where patients in the younger age group (25-35 years old) were at higher risk of lower back pain, while participants in the older age group (36 to 44 years old and 45 years or older) were at higher risk of musculoskeletal pain in two different sites.Musculoskeletal pain affects more than two-thirds of faculty members. In particular, low back pain is a common problem among faculty members. Age is a significant risk factor for the occurrence of musculoskeletal pain, with more than one site involvement in older age.

Upper gastrointestinal tract involvement in the management of bariatric patients in the Kingdom of Saudi Arabia.

BACKGROUND: Preoperative esophagogastroduodenoscopy (EGD) may affect the management of bariatric patients although this is not consistent universally. The present prospective study evaluated the effect of preoperative EGD findings in obese Saudi patients, including upper digestive symptoms (UDS) and comorbidities, on their planned surgery. METHODS: From January 2018 to May 2019, we conducted a 4-center retrospective observational study to evaluate the endoscopic findings among Saudi patients aged 18-65 years with a body mass index (BMI) >40 kg/m2. Preoperative data included UDS, comorbidities, Helicobacter pylori (H. pylori) infection assessed during a histopathological examination, and EGD findings. RESULTS: 717 patients underwent EGDs, and 432 underwent bariatric surgery. The mean BMI was 44.3±6.3 kg/m2, and the mean age was 27.8±11.8 years. The overall UDS prevalence was 49%, with the most frequent being gastroesophageal reflux disease 54% (387/717), followed by dyspepsia 44% (315/717). H. pylori infection was detected in 287/672 (42.4%) patients. The total percentage of patients with normal EGD was 36% (258/717). A delayed bariatric procedure was performed in 15% of the patients for the following reasons: 2.3% had large polyps of >1 cm (either hyperplastic or cystic polyps); 1.62% had esophagitis grade C and D based on the Los Angeles classification; 0.7% had Barrett's esophagus; and 5.7% had peptic ulcer disease. CONCLUSIONS: Our findings confirmed that obesity carries a profound health burden with a significant impact on health expenditures. Routine preoperative EGD in the obese Saudi population appears to be mandatory to identify factors that may change, delay, or postpone the bariatric procedure.

Corrigendum to "New terpenic and phenolic compounds from Suaeda monoica reverse oxidative and apoptotic damages in human endothelial cells". [Saudi Pharm. J. 29(10) (2021) 1102-1111].

[This corrects the article DOI: 10.1016/j.jsps.2021.08.007.].

Oncoglabrinol C, a new flavan from Oncocalyx glabratus protects endothelial cells against oxidative stress and apoptosis, and modulates hepatic CYP3A4 activity.

Active herbal or natural compounds have high chemical diversity and specificity than synthetic drugs. Recently, we have validated the hypoglycemic salutation of Oncocalyx glabratus in rodent model, and demonstrated the activation of PPARα/γ by its newly ioslated flavan derivative Oncoglabrinol C (5,3'-Dihydroxyflavan 7-4'-O-digallate) in liver cells (HepG2). Here we evaluated the potential of Oncoglabrinol C against Dichlorofluorescin (DCFH) and Methylglyoxal (MGO) induced endothelial cells (HUVEC) oxidative and apoptotic damage, including activation of PXR-mediated hepatic CYP3A4. Our MTT assay showed protection of ~57% and ~63.5% HUVEC cells by 10 and 20 µg/ml doses of Oncoglabrinol C, respectively through attenuating DCFH triggered free-radicals. Also, the two doses effectively protected ~53% and ~65.5% cells, respectively by reversing MGO toxicity. In DCFH and MGO treated cells, Oncoglabrinol C (20 µg/ml) effectively downregulated caspase 3/7 activity by ~33% and ~43.5%, respectively. Moreover, in reporter gene (dual-luciferase) assay, Oncoglabrinol C (20 µg/ml) moderately activated hepatic CYP3A4. Molecular docking of Oncoglabrinol C indicated its strong interactions with cellular caspase 3/7, PPARα/γ and PXR proteins, which supported its anti-apoptotic (antagonistic) as well as pro-hypoglycemic and PXR/CYP activating (agonistic) activities. Taken together, our findings demonstrated the potential of Oncoglabrinol C in reversing the endothelial oxidative and apoptotic damage as well as in the activation of hepatic CYP3A4. This warrants further evaluations of Oncoglabrinol C and related compounds towards developing effective and safe drugs against diabetes associated cardiovascular disorders.

Functional implications of pH-induced conformational changes in the Sphingosine kinase 1.

Sphingosine kinase 1 (SphK1) catalyzes the conversion of sphingosine to sphingosine-1-phosphate that acts as a bioactive signalling molecule, and regulates various cellular processes including lymphocyte trafficking, angiogenesis and response to apoptotic stimuli. Abnormal expression of SphK1 has been observed in a wide range of cancers highlighting their role in tumour growth and metastasis. This enzyme also plays a critical role in metabolic and inflammatory diseases, including pulmonary fibrosis, diabetic neuropathy and Alzheimer's disease. In the present study, we have investigated the structural and conformational changes in SphK1 at varying pH using various spectroscopic techniques. Consistent results were observed with the function of SphK1 at corresponding pH values. SphK1 maintains its secondary and tertiary structure in the pH range of 7.5-10.0. However, protein aggregation was observed in the acidic pH range (4.0-6.5). At pH 2.0, the SphK1 exists in the molten-globule state. Kinase assay also shows that SphK1 activity was optimal in the pH range of 7.5-8.5. To complement in vitro results, we have performed 100 ns molecular dynamics simulation to examine the effect of pH on the structural stability of SphK1 at molecular level. SphK1 maintains its native conformation in the alkaline pH range with some residual fluctuations detected at acidic pH. A considerable correlation was noticed between spectroscopic, enzymatic activity and MD simulation studies. pH dependent structural changes can be further implicated to understand its association with disease condition, and cellular homeostasis with respect to protein function under variable pH conditions.

Identification and evaluation of glutathione conjugate gamma-l-glutamyl-l-cysteine for improved drug delivery to the brain.

Glutathione (GU), an endogenous antioxidant tripeptide, is frequently transferred in the human brain through N-methyl-d-aspartate receptor (NMDAR), profusely expressed at the blood-brain barrier (BBB) junction. GU, also modifies the characteristics of tight junction proteins (occludin and claudin) at the site of BBB by depolarizing the enzyme, protein tyrosine phosphatase that manifests its usefulness for passive delivery of nanocarriers to the brain. GU, thus, represents itself as an ideal ligand for the surface decoration of nanocarriers to successfully administer them across the brain via receptor-mediated drug delivery pathway. Hence, we have employed here, in-silico approaches to identify the potential GU-like molecules, as appropriate ligand(s) for surface engineering of nanoconstruct with the purpose of attaining targeted drug delivery to the brain. Structure-based virtual screening methods was used to filter PubChem database for the identification of bioactive compounds with >95% structure similarity with GU. We have further screened the compounds against NMDAR using molecular docking approach. Top hits were selected based on their high binding affinities and selectivity towards NMDAR, and their binding pattern was analysed in detail. Finally, all atom molecular dynamics simulation for 100 ns was carried out on free NMDAR and in-presence of the selected GU-like compound, gamma-l-glutamyl-l-cysteine to evaluate complex stability and structural dynamics. In conclusion, gamma-l-glutamyl-l-cysteine may act as potential binding partner of NMDAR which can further be evaluated in drug delivery system to brain across the BBB.Communicated by Ramaswamy H. Sarma.

Evaluation of pyrazolopyrimidine derivatives as microtubule affinity regulating kinase 4 inhibitors: Towards therapeutic management of Alzheimer's disease.

Microtubule affinity regulating kinase 4 (MARK4) plays essential role in the tau-assisted regulation of microtubule dynamics. Over expression of MARK4 causes early phosphorylation of Ser262 of tau protein which is essential for microtubule binding. Hyperphosphorylation of tau protein causes the formation of paired helical fragments and neurofibrillary tangles, the hallmarks of Alzheimer's disease. Targeting the modulation of MARK4 activity is an effective strategy for therapeutic intervention of Alzheimer's and other MARK4 associated neurodegenerative diseases. Having role of pyrazolopyrimidine derivatives in the therapeutic management of neurodegenerative diseases, we have tried to estimate their binding affinity with the MARK4. We performed in silico screening of 59 pyrazolopyrimidine derivatives against MARK4 and obtained a few best possible inhibitors. Molecular docking-based interaction analysis suggested five potential leads that were further analyzed using molecular dynamics simulations, MM/PBSA, principal component analysis and graph theory based dynamic network analysis to observe structural changes caused due to ligand binding. All these computational analyses suggested that compounds with PubChem IDs: 91895678, 91895679, 91895692, 91145515 and 90794095 may be further exploited to address Alzheimer's and other neurodegenerative diseases.Communicated by Ramaswamy H. Sarma.

The anti-hepatitis B virus therapeutic potential of anthraquinones derived from Aloe vera.

Although the approved hepatitis B virus (HBV)-polymerase inhibitors (e.g., lamivudine) often lead to drug-resistance, several natural products have shown promising efficacies. Though Aloe vera (AV) gel and its constituents are shown inhibitors of many viruses, their anti-HBV activity still remains elusive. We therefore, tested the anti-HBV potential of AV extract and its anthraquinones in hepatoma cells, including molecular docking, high-performance thin layer chromatography (HPTLC), and cytochrome P450 (CYP3A4) activation analyses. Our anti-HBV assays (HBsAg/HBeAg Elisa) showed maximal inhibition of viral antigens production by aloe-emodin (~83%) > chrysophanol (~62%) > aloin B (~61%) > AV extract (~37%) in HepG2.2.15 cells. Interestingly, the effect of aloe-emodin was comparable with lamivudine (~86%). Moreover, sequential treatment with lamivudine (pulse) followed by aloe-emodin (chase) enhanced the efficacy of monotherapy by ~12%. Docking (AutoDock Vina) of the anthraquinones indicated strong interactions with HBV-polymerase residues that formed stable complexes with high Gibbs's free energy. Further, identification of aloe-emodin and aloin B by validated HPTLC in AV extract strongly endorsed its anti-HBV potential. In addition, our luciferase-reporter gene assay of transfected HepG2 cells showed moderate induction of CYP3A4 by aloe-emodin. In conclusion, this is the first report on anti-HBV potential of AV-derived anthraquinones, possibly via HBV-polymerase inhibition. Of these, although aloin B exhibits novel antiviral effect, aloe-emodin appears as the most promising anti-HBV natural drug with CYP3A4 activating property towards its enhanced therapeutic efficacy.

Structural Analysis and Conformational Dynamics of STN1 Gene Mutations Involved in Coat Plus Syndrome.

The human CST complex (CTC1-STN1-TEN1) is associated with telomere functions including genome stability. We have systemically analyzed the sequence of STN and performed structure analysis to establish its association with the Coat Plus (CP) syndrome. Many deleterious non-synonymous SNPs have been identified and subjected for structure analysis to find their pathogenic association and aggregation propensity. A 100-ns all-atom molecular dynamics simulation of WT, R135T, and D157Y structures revealed significant conformational changes in the case of mutants. Changes in hydrogen bonds, secondary structure, and principal component analysis further support the structural basis of STN1 dysfunction in such mutations. Free energy landscape analysis revealed the presence of multiple energy minima, suggesting that R135T and D157Y mutations destabilize and alter the conformational dynamics of STN1 and thus may be associated with the CP syndrome. Our study provides a valuable direction to understand the molecular basis of CP syndrome and offer a newer therapeutics approach to address CP syndrome.

Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: Cell culture and molecular docking study.

Despite high anti-HBV efficacies, while the nucleoside analogs (e.g., lamivudine) lead to the emergence of drug-resistance, interferons (e.g., IFN-α causes adverse side-effects. Comparatively, various natural or plant products have shown similar or even better efficacy. Hence, new antiviral strategies must focus not only on synthetic molecules but also on potential natural compounds. In this report, we have combined the in vitro cell culture and in silico molecular docking methods to assess the novel anti-HBV activity and delineate the inhibitory mechanism of selected plant-derived pure compounds of different classes. Of the tested (2.5-50 µg/ml) twelve non-cytotoxic compounds, ten (10 µg/ml) were found to maximally inhibit HBsAg production at day 5. Compared to quercetin (73%), baccatin III (71%), psoralen (67%), embelin (65%), menisdaurin (64%) and azadirachtin (62%) that showed high inhibition of HBeAg synthesis, lupeol (52%), rutin (47%), ß-sitosterol (43%) and hesperidin (41%) had moderate efficacies against HBV replication. Further assessment of quercetin in combination with the highly active compounds, enhanced its anti-HBV activity up to 10%. Being the most important drug target, a 3-D structure of HBV polymerase (Pol/RT) was modeled and docked with the active compounds, including lamivudine as standard. Docking of lamivudine indicated strong interaction with the modeled HBV Pol active-site residues that formed stable complex (∆G = -5.2 kcal/mol). Similarly, all the docked antiviral compounds formed very stable complexes with HBV Pol (∆G = -6.1 to -9.3 kcal/mol). Taken together, our data suggest the anti-HBV potential of the tested natural compounds as novel viral Pol/RT inhibitors.