In silico identification of phytochemical inhibitors for multidrug-resistant tuberculosis based on novel pharmacophore generation and molecular dynamics simulation studies.

BACKGROUND: Multidrug-resistant tuberculosis (particularly resistant to pyrazinoic acid) is a life-threatening chronic pulmonary disease. Running a marketed regime specifically targets the ribosomal protein subunit-1 (RpsA) and stops trans-translation in the non-mutant bacterium, responsible for the lysis of bacterial cells. However, in the strains of mutant bacteria, this regime has failed in curing TB and killing pathogens, which may only because of the ala438 deletion, which inhibit the binding of pyrazinoic acid to the RpsA active site. Therefore, such cases of tuberculosis need an immediate and effective regime. OBJECTIVE: This study has tried to determine and design such chemotypes that are able to bind to the mutant RpsA protein. METHODS: For these purposes, two phytochemical databases, i.e., NPASS and SANCDB, were virtually screened by a pharmacophore model using an online virtual screening server Pharmit. RESULTS: The model of pharmacophore was developed using the potential inhibitor (zr115) for the mutant of RpsA. Pharmacophore-based virtual screening results into 154 hits from the NPASS database, and 22 hits from the SANCDB database. All the predicted hits were docked in the binding pocket of the mutant RpsA protein. Top-ranked five and two compounds were selected from the NPASS and SANCDB databases respectively. On the basis of binding energies and binding affinities of the compounds, three compounds were selected from the NPASS database and one from the SANCDB database. All compounds were found to be non-toxic and highly active against the mutant pathogen. To further validate the docking results and check the stability of hits, molecular dynamic simulation of three compounds were performed. The MD simulation results showed that all these finally selected compounds have stronger binding interactions, lesser deviation or fluctuations, with greater compactness compared to the reference compound. CONCLUSION: These findings indicate that these compounds could be effective inhibitors for mutant RpsA.

Prevalence and Risk Factors of Voice Disorders Among Teachers in Saudi Arabia.

Introduction Voice is a crucial tool for communication, and voice problems are more likely to occur in professionals who frequently use their voice for work. Teachers, whose profession requires sustained vocal use, are particularly susceptible to occupation-related voice disorders. This study aimed to quantify the prevalence of voice disorders among teachers in Saudi Arabia, with the general population serving as a control group, and to identify associated risk factors. Methods A cross-sectional study was conducted utilizing an online self-administered questionnaire, which was completed by both teachers and the general population in Saudi Arabia. The latter group acted as a control. The questionnaire included sections on sociodemographic data, teaching patterns, symptoms of voice issues, and the Voice Handicap Index-10 (VHI-10) for assessing voice disorders among participants. Results The study included 640 participants, with 438 (68.4%) being teachers, the majority of whom were females (N = 406; 63.4%). The most common voice-related symptoms reported by teachers were hoarseness (N = 210; 37.9%) and dry throat (N = 147; 26.9%). Voice disorders, as determined by the VHI, affected 355 (55.5%) of the teachers. A high VHI score was associated with a diagnosis of voice disorders and GERD. There was no significant difference in the VHI scores between teachers and the general population (p > 0.05). Conclusion Teachers in Saudi Arabia exhibited a higher prevalence of voice disorders compared to the general population. Risk factors, such as smoking, longer teaching experience, and more teaching hours per week, were more common among teachers with voice disorders. Further investigative studies are warranted to elucidate the causal relationships between these variables and voice disorders.

Structure-based investigation of pyruvate dehydrogenase kinase-3 inhibitory potential of thymoquinone, targeting lung cancer therapy.

Protein kinases are an attractive therapeutic target for cardiovascular, cancer and neurodegenerative diseases. Cancer cells demand energy generation through aerobic glycolysis, surpassing "oxidative phosphorylation" (OXPHOS) in mitochondria. The pyruvate dehydrogenase kinases (PDKs) have many regulatory roles in energy generation balance by controlling the pyruvate dehydrogenase complex. Overexpression of PDKs is associated with the overall survival of cancer. PDK3, an isoform of PDK is highly expressed in various cancer types, is targeted for inhibition in this study. PDK3 has been shown to binds strongly with a natural compound, thymoquinone (TQ), which is known to exhibit anti-cancer potential. Detailed interaction between the PDK3 and TQ was carried out using spectroscopic and docking methods. The overall changes in the protein's structures after TQ binding were estimated by UV-Vis spectroscopy, circular dichroism and fluorescence binding studies. The kinase activity assay was also carried out to see the kinase inhibitory potential of TQ. The enzyme inhibition assay suggested an excellent inhibitory potential of TQ towards PDK3 (IC50 = 5.49 µM). We observed that TQ forms a stable complex with PDK3 without altering its structure and can be a potent PDK3 inhibitor which may be implicated in cancer therapy after desired clinical validation.

Prospective virtual screening combined with bio-molecular simulation enabled identification of new inhibitors for the KRAS drug target.

Lung cancer is a disease with a high mortality rate and it is the number one cause of cancer death globally. Approximately 12-14% of non-small cell lung cancers are caused by mutations in KRASG12C. The KRASG12C is one of the most prevalent mutants in lung cancer patients. KRAS was first considered undruggable. The sotorasib and adagrasib are the recently approved drugs that selectively target KRASG12C, and offer new treatment approaches to enhance patient outcomes however drug resistance frequently arises. Drug development is a challenging, expensive, and time-consuming process. Recently, machine-learning-based virtual screening are used for the development of new drugs. In this study, we performed machine-learning-based virtual screening followed by molecular docking, all atoms molecular dynamics simulation, and binding energy calculations for the identifications of new inhibitors against the KRASG12C mutant. In this study, four machine learning models including, random forest, k-nearest neighbors, Gaussian naïve Bayes, and support vector machine were used. By using an external dataset and 5-fold cross-validation, the developed models were validated. Among all the models the performance of the random forest (RF) model was best on the train/test dataset and external dataset. The random forest model was further used for the virtual screening of the ZINC15 database, in-house database, Pakistani phytochemicals, and South African Natural Products database. A total of 100 ns MD simulation was performed for the four best docking score complexes as well as the standard compound in complex with KRASG12C. Furthermore, the top four hits revealed greater stability and greater binding affinities for KRASG12C compared to the standard drug. These new hits have the potential to inhibit KRASG12C and may help to prevent KRAS-associated lung cancer. All the datasets used in this study can be freely available at ( https://github.com/Amar-Ajmal/Datasets-for-KRAS ).

Rural households' livelihood adaptation strategies in the face of changing climate: A case study from Pakistan.

Rural and agricultural communities' adaptation to climate change has gained significant attention owing to many countries' vulnerability to climate change risks. A similar trend has been witnessed in South Asia, a highly climate-vulnerable region, where research has grown dramatically considering the agriculture sector's vulnerability to climate-induced disasters. However, little attention has been paid to the adaptation of the livelihoods of rural households. This research, therefore, takes the case of Pakistan to explore livelihood adaptation strategies of rural households to climate change and investigate the factors that expedite or halt the adoption of livelihood diversification strategies. A multistage sampling design is used in this research, where 480 rural households from the Punjab province of Pakistan were selected and interviewed using stratified and random sampling approaches. A multivariate probit (MVP) regression model is employed to analyze the factors affecting households' adoption of livelihood adaptation strategies. The results show that besides adaptation of agronomic operations (agricultural adaptation strategies), rural households in the study area employed a wide range of strategies to adapt their livelihoods to climate change. These strategies include poultry and livestock farming, value addition of farm produce, trading of animals and farm commodities, small businesses (shops, etc.), daily wage labor, horticultural crop farming, and non-farming jobs. The estimates of the MVP model revealed that respondents' education, household size, income, access to a credit facility, access to farm advisory services, and access to climate forecasts have significantly influenced the choice of livelihood adaptation strategies. Based on these findings, this research recommends that the authorities should make efforts to improve farmers' understanding of the adaptation of climate change risks and educate them to adopt multiple livelihood options to improve the resilience of their livelihoods to climate-induced risks. This research has important policy implications for other countries with similar socio-economic features.

Awareness of Bariatric Sleeve Gastrectomy Complications Among the General Population of Saudi Arabian Regions.

Sleeve gastrectomy (SG) is a type of procedure called bariatric surgery that provides large weight loss and has a positive impact on diseases associated with obesity. However, it has brought several complications that have an impact on those undergoing surgery, which are classified into intraoperative and postoperative issues. The study's goal is to assess the Saudi Arabian population's awareness of SG consequences. This study assessed the general population's knowledge in Saudi Arabia in 2023 using a cross-sectional approach. The total number of participants was 1,013, the majority of whom were individuals between the ages of 18 and 25 (471, 46%), and females (692, 68%). A total of 692 (68%) participants showed awareness of BMI; in addition, 987 (97%) were aware of gastric sleeve surgery, and 538 (53%) understood its indications correctly. Regarding SG complications, approximately 821 (81%) of participants showed awareness. There were significant associations between knowledge of gastric sleeve surgery and residence in the northern region of Saudi Arabia. In conclusion, our study indicated that the general population is aware of the complications of gastric sleeve surgery, but it found a deficiency in their knowledge about BMI.

Exploring the promising potential of noscapine for cancer and neurodegenerative disease therapy through inhibition of integrin-linked kinase-1.

Integrin-linked kinase (ILK), a ß1-integrin cytoplasmic domain interacting protein, supports multi-protein complex formation. ILK-1 is involved in neurodegenerative diseases by promoting neuro-inflammation. On the other hand, its overexpression induces epithelial-mesenchymal transition (EMT), which is a major hallmark of cancer and activates various factors associated with a tumorigenic phenotype. Thus, ILK-1 is considered as an attractive therapeutic target. We investigated the binding affinity and ILK-1 inhibitory potential of noscapine (NP) using spectroscopic and docking approaches followed by enzyme inhibition activity. A strong binding affinity of NP was measured for the ILK-1 with estimated Ksv (M-1) values of 1.9 × 105, 3.6 × 105, and 4.0 × 105 and ∆G0 values (kcal/mol) -6.19554, -7.8557 and -8.51976 at 298 K, 303 K, and 305 K, respectively. NP binds to ILK-1 with a docking score of -6.6 kcal/mol and forms strong interactions with active-site pocket residues (Lys220, Arg323, and Asp339). The binding constant for the interaction of NP to ILK-1 was 1.04 × 105 M-1, suggesting strong affinity and excellent ILK-1 inhibitory potential (IC50 of ∼5.23µM). Conformational dynamics of ILK-1 were also studied in the presence of NP. We propose that NP presumably inhibits ILK-1-mediated phosphorylation of various downstream signalling pathways that are involved in cancer cell survival and neuroinflammation.

Structural and energetic analysis of NS5 protein inhibition by small molecules in Japanese encephalitis virus using machine learning and steered molecular dynamics approach.

One of the viral diseases that affect millions of people around the world, particularly in developing countries, is Japanese encephalitis (JE). In this study, the conserved protein of this virus, that is, non-structural protein 5 (NS5), was used as a target protein for this study, and a compound library of 749 antiviral molecules was screened against NS5. The current study employed machine learning-based virtual screening combined with molecular docking. Here, three hits (24360, 123519051 and 213039) had lower binding energies (< -8 kcal/mol) than the control, S-Adenosyl-L-homocysteine (SAH). All the compounds showed significant H-bond interactions with functional residues, which were also observed by the control. Molecular dynamics simulation, MM/GBSA for binding free energy analysis, principal component analysis and free energy landscape were also performed to study the stability of the complex formation. All three compounds had similar root mean square deviation trends, which were comparable to the control, SAH. Post-MD, the 123519051-receptor complex had the highest number of H-bonds (4 to 5) after the control, out of which three exhibited the highest percentage occupancy (50%, 24% and 79%). Both docking and MD, 123519051 showed an H-bond with the residue Gly111, which was also found for the control-protein complex. 123519051 showed the lowest binding free energy with ΔGbind of -89 kJ/mol. Steered molecular dynamics depicted that 123519051 had the maximum magnitude of dissociation (1436.43 kJ/mol/nm), which was more than the control, validating its stable complex formation. This study concluded that 123519051 is a binder and could inhibit the protein NS5 of JE.Communicated by Ramaswamy H. Sarma.

Identification of potential therapeutic targets for COVID-19 through a structural-based similarity approach between SARS-CoV-2 and its human host proteins.

Background: The COVID-19 pandemic caused by SARS-CoV-2 has led to millions of deaths worldwide, and vaccination efficacy has been decreasing with each lineage, necessitating the need for alternative antiviral therapies. Predicting host-virus protein-protein interactions (HV-PPIs) is essential for identifying potential host-targeting drug targets against SARS-CoV-2 infection. Objective: This study aims to identify therapeutic target proteins in humans that could act as virus-host-targeting drug targets against SARS-CoV-2 and study their interaction against antiviral inhibitors. Methods: A structure-based similarity approach was used to predict human proteins similar to SARS-CoV-2 ("hCoV-2"), followed by identifying PPIs between hCoV-2 and its target human proteins. Overlapping genes were identified between the protein-coding genes of the target and COVID-19-infected patient's mRNA expression data. Pathway and Gene Ontology (GO) term analyses, the construction of PPI networks, and the detection of hub gene modules were performed. Structure-based virtual screening with antiviral compounds was performed to identify potential hits against target gene-encoded protein. Results: This study predicted 19,051 unique target human proteins that interact with hCoV-2, and compared to the microarray dataset, 1,120 target and infected group differentially expressed genes (TIG-DEGs) were identified. The significant pathway and GO enrichment analyses revealed the involvement of these genes in several biological processes and molecular functions. PPI network analysis identified a significant hub gene with maximum neighboring partners. Virtual screening analysis identified three potential antiviral compounds against the target gene-encoded protein. Conclusion: This study provides potential targets for host-targeting drug development against SARS-CoV-2 infection, and further experimental validation of the target protein is required for pharmaceutical intervention.

Management of 'floating arm': a case report of adolescent ipsilateral proximal humerus fracture with open distal complex intraarticular fracture.

Simultaneous ipsilateral fractures of the proximal and distal humerus, known as 'floating arm', are rarely seen in adolescents and are considered challenging to manage. Most of the published cases have involved proximal humerus and distal supracondylar fractures. This paper presents a special case of floating arm injury in a 14-year-old boy following a motor vehicle accident that was managed in a well-established trauma center. The injury consisted of displaced proximal humerus and open distal T-condylar intraarticular fractures. The patient was discharged in good condition and regained functionality with no reported complications.

The assessment of knowledge and awareness about iron deficiency anemia among the population of Riyadh province.

Background: Iron deficiency anemia (IDA) is considered the most common micronutrient deficiency and the greatest health concern throughout the globe. The main causes of anemia are iron deficiency, parasitic infestations, viral infections (human immunodeficiency virus), hemorrhage, and renal and hepatic diseases. Therefore, it is mandatory to be equipped with the proper knowledge regarding the causes, signs, symptoms, and diets containing iron, which can be a good initiative for the proper treatment and management of the health hazards; also, it will help primary care physicians to differentiate the degree of the disease and further treatment, planning, and management. The recent study was performed to understand the level of knowledge and awareness about IDA and its causes, prevention, and treatment. Methods: The study was carried out through an online survey using Google forms, which were distributed to the population residing in Riyadh Province. Results and Discussion: The responses received about the knowledge regarding IDA and its symptoms indicated weakness [565 (52.9%)], cold hands and feet [593 (55.5%)], and hair loss [663 (62.1)], and the majority (84.3%) of the participants believed that the major cause for IDA is malnutrition. Conclusion and Recommendations: Conclusively, it was believed that the presented study will be helpful to primary care physicians, the patients suffering from IDA, and the general population with a better understanding of the causes, additional signs and symptoms, proper treatment, timely management, sources of iron, and how to avoid the worse outcomes and complications of the disease. It will also help the health agencies in the kingdom to set further planning for the treatment and management of the disease through awareness platforms.

Inappropriate Subcutaneous Implantable Cardioverter-defibrillator Shocks-A Rare Case of Triple Counting.

Sudden cardiac death (SCD) caused by ventricular tachyarrhythmias is a significant contributor to cardiovascular deaths worldwide. Implantable cardioverter-defibrillators (ICDs) have shown efficacy in preventing and reducing mortality from SCD, but traditional transvenous ICDs have inherent challenges and drawbacks, such as lead fractures, lead-associated endocarditis, and lead failure. To address these issues, subcutaneous ICDs (S-ICDs) have been developed. S-ICDs lack pacing capacity but are a valid alternative for patients at high risk for infection or with difficult venous access. Pre-implantation screening can help prevent inappropriate device shocks. We present a case in which a patient received inappropriate S-ICD therapy, which was attributed to the triple counting of P-, R-, and T-waves in a patient with sinus rhythm. This is an unusual occurrence, and, to the best of our knowledge, there are only a limited number of case reports documenting inappropriate shocks due to the oversensing of P-waves and T-waves.

Identification of novel STAT3 inhibitors for liver fibrosis, using pharmacophore-based virtual screening, molecular docking, and biomolecular dynamics simulations.

The signal transducer and activator of transcription 3 (STAT3) plays a fundamental role in the growth and regulation of cellular life. Activation and over-expression of STAT3 have been implicated in many cancers including solid blood tumors and other diseases such as liver fibrosis and rheumatoid arthritis. Therefore, STAT3 inhibitors are be coming a growing and interesting area of pharmacological research. Consequently, the aim of this study is to design novel inhibitors of STAT3-SH3 computationally for the reduction of liver fibrosis. Herein, we performed Pharmacophore-based virtual screening of databases including more than 19,481 commercially available compounds and in-house compounds. The hits obtained from virtual screening were further docked with the STAT3 receptor. The hits were further ranked on the basis of docking score and binding interaction with the active site of STAT3. ADMET properties of the screened compounds were calculated and filtered based on drug-likeness criteria. Finally, the top five drug-like hit compounds were selected and subjected to molecular dynamic simulation. The stability of each drug-like hit in complex with STAT3 was determined by computing their RMSD, RMSF, Rg, and DCCM analyses. Among all the compounds Sa32 revealed a good docking score, interactions, and stability during the entire simulation procedure. As compared to the Reference compound, the drug-like hit compound Sa32 showed good docking scores, interaction, stability, and binding energy. Therefore, we identified Sa32 as the best small molecule potent inhibitor for STAT3 that will be helpful in the future for the treatment of liver fibrosis.

Unravelling the role of microneedles in drug delivery: Principle, perspectives, and practices.

In recent year, the research of transdermal drug delivery systems has got substantial attention towards the development of microneedles (MNs). This shift has occurred due to multifaceted advantages of MNs as they can be utilized to deliver the drug deeper to the skin with minimal invasion, offer successful delivery of drugs and biomolecules that are susceptible to degradation in gastrointestinal tract (GIT), act as biosensors, and help in monitoring the level of biomarkers in the body. These can be fabricated into different types based on their applications as well as material for fabrication. Some of their types include solid MNs, hollow MNs, coated MNs, hydrogel forming MNs, and dissolving MNs. These MNs deliver the therapeutics via microchannels deeper into the skin. The coated and hollow MNs have been found successful. However, they suffer from poor drug loading and blocking of pores. In contrast, dissolving MNs offer high drug loading. These MNs have also been utilized to deliver vaccines and biologicals. They have also been used in cosmetics. The current review covers the different types of MNs, materials used in their fabrication, properties of MNs, and various case studies related to their role in delivering therapeutics, monitoring level of biomarkers/hormones in body such as insulin. Various patents and clinical trials related to MNs are also covered. Covered are the major bottlenecks associated with their clinical translation and potential future perspectives.

Rational design of multi-epitope-based vaccine by exploring all dengue virus serotypes proteome: an immunoinformatic approach.

Millions of people's lives are being devastated by dengue virus (DENV), a severe tropical and subtropical illness spread by mosquitoes and other vectors. Dengue fever may be self-limiting like a common cold or can rapidly progress to catastrophic dengue hemorrhagic fever or dengue shock syndrome. With four distinct dengue serotypes (DENV1-4), each with the potential to contain antibody-boosting complicated mechanisms, developing a dengue vaccine has been an ambitious challenge. Here, we used a computational pan-vaccinomics-based vaccine design strategy (reverse vaccinology) for all 4 DENV serotypes acquired from different regions of the world to develop a new and safe vaccine against DENV. Consequently, only five mapped epitopes from all the 4 serotypes were shown to be extremely effective for the construction of multi-epitope vaccine constructs. The suggested vaccine construct V5 from eight vaccine models was thus classified as an antigenic, non-allergenic, and stable vaccine model. Moreover, molecular docking and molecular dynamics simulation was performed for the V5 vaccine candidate against the HLAs and TRL2 and 4 immunological receptors. Later, the vaccine sequence was transcribed into the cDNA to generate an expression vector for the Escherichia coli K12 strain. Our research suggests that this vaccine design (V5) has promising potential as a dengue vaccine. However, further experimental analysis into the vaccine's efficacy might be required for the V5 proper validation to combat all DENV serotypes.

Acaricidal assessment of the fungal extract of Pleurotus ostreatus against Rhipicephalus microplus: Role of in vitro and in silico analysis.

The Pleurotus ostreatus mushroom, commonly referred to as the oyster mushroom, is a widely consumed edible mushroom that grows in clusters on dead or dying trees. In addition to its culinary uses, research has found that the mushroom may also have potential medicinal properties. The current study investigated the potential use of a fungal extract from P. ostreatus as a natural acaricide against Rhipicephalus microplus, a major vector of economically significant infections and one of the most significant bovine ectoparasites. The study used the adult immersion test (AIT) and the larvae packet test (LPT) to evaluate the effectiveness of the extract against ticks. To evaluate the reproductive effect of the fungal extract on the reproduction of R. microplus engorged females, the eggs were tested for weight and egg-laying index. The results of the study showed that P. ostreatus extract had a significant acaricidal effect, with a 40 mg/mL concentration causing 89 ± 2.64% mortality in R. microplus larvae compared to the 91.00 ± 3.60% mortality by the positive control at 48 h interval. Whereas in the AIT, the extract inhibited 39.86 ± 4.13% of oviposition. The study also used in silico approach to further examine the binding mechanisms of the compounds in the fungal extract to the target protein R. microplus Triosephosphate isomerase RmTIM, using molecular docking in AutoDock Vina software. Docking scores of -8.3, -7.7 and -6.9 kcal/mol, respectively, showed that rutin, naringin and myricitin had significant interactions with the active site residues of the target protein. Our results suggest that P. ostreatus extract may be a potential alternative to traditional acaricides for controlling R. microplus in livestock.

Households food consumption pattern in Pakistan: Evidence from recent household integrated economic survey.

The analysis of food consumption pattern is a primary concern of any developing country because it is related with food security. Pakistan is one of the emerging nations of the developing world. Due to the similarities and differences in households' food consumption behavior, income distribution, the effects of alternative tax structures, cost-benefit analyses, and the choice of cost of living index, the study of households' food consumption pattern is crucial for a developing nation like Pakistan. Furthermore, for Pakistan's food security in the present and the future, an analysis of food consumption pattern is crucial. The main objective of this study is to analyze the households' food consumption pattern. Linear Approximation Almost Ideal Demand System (LA/AIDS) is applied using data from Household Integrated Economic Survey (HIES) for the year 2018-19. This study makes a significant contribution by estimating household age composition elasticities, which were absent from earlier studies. Results from the income elasticities reveal that milk, meat, and fruits are luxuries food items. Similarly, on the basis of inelastic income elasticities we declared cereals, pulses, vegetables, sugar, and ghee as necessity food items. Results from the compensated own price elasticities show that the eight food commodity groups have inelastic own-price elasticities. This implies that these food commodities are integral food items of household diet. Results from the compensated cross-price elasticities shows that cereals and pulses, cereals and vegetables, pulses and vegetables, milk and fruits, meat and fruits, and milk and ghee are gross substitutes. On the other hand, pulses and meat, pulses and fruits, and ghee and meat are gross complements. According to the findings of the household age composition elasticities, adding children to a household significantly increases its sugar consumption while significantly reducing its fruit consumption. Any increase in the size of the household by an adolescent, adult, or a person in their middle age results in a significant increase in the consumption of cereals and a significant drop in the consumption of fruits. Finally, any increase in the size of the households brought about by an elder resulted in a significant rise in the consumption of cereals and a significant drop in the consumption of vegetables.

Congenital pulmonary airway malformation complicated by aspergilloma: A rare adulthood presentation - Case report.

Congenital Pulmonary Airway Malformation (CPAM) is an uncommon condition in adults, which typically presents as acute fever and lung abscesses caused by bacterial infections. We present a case of a 39-year-old female with a CPAM in the upper lobe of the right lung, complicated by an aspergilloma, who presented with a history of hemoptysis. The patient underwent an upper lobectomy and is symptom-free in follow-up. 2012 Elsevier Ltd. All rights reserved.

Hepatitis B virus infection, structure, genotypes, and epidemiology - A review

There are currently 250 million people infected with the hepatitis B virus (HBV) worldwide, despite the availability of a prophylactic vaccine for many years and the use of efficient and well-tolerated viral suppressive drugs since 1998. In this review, I go through the most recent developments in the structure, and epidemiology and biology of the virus, look at changes in the way the disease is currently being treated, and investigate novel, cutting-edge treatments that are being developed for the treatment of HBV infection. Genotypes and serological subtypes have a strong and statistically significant association, and in some circumstances, serological subtypes can be utilized to distinguish between sub genotypes. geographic distribution of certain genotypes and subgenotypes varies and plays a crucial role in the clinical manifestation of infection as well as the response to antiviral medication. Thanks to advancements in genetics, the prospect for vaccinations, and tailored management to target the integration of virus with host. HBV persistence occurs due to covalently closed circular DNA can rarely be removed by current pharmacological therapies. Alternative treatment approaches, such as those built on silencing of viral. According to reports, HBV DNA levels can be inhibited and conversion of HBeAg to antibody to HBe Ag can be induced by antiviral medication like nucleotide analog (NUC), which can prevent liver-related death. Additionally, there is a critical need for the creation of global archives of standardized HBV reagents and protocols that can be accessible by all HBV researchers. The plan for HBV cure research presented in this position paper will make a significant contribution to the objective of eradicating HBV infection globally. (AU)

Identification of potential Escherichia coli DNA gyrase B inhibitors targeting antibacterial therapy: an integrated docking and molecular dynamics simulation study.

The alarming rise in the rate of antibiotic resistance is a matter of significant concern. DNA gyrase B (GyrB), a critical bacterial enzyme involved in DNA replication, transcription, and recombination, has emerged as a promising target for antibacterial agents. Inhibition of GyrB disrupts bacterial DNA replication, leading to cell death, making it an attractive candidate for antibiotic development. Although several classes of antibiotics targeting GyrB are currently in clinical use, the emergence of antibiotic resistance necessitates the exploration of novel inhibitors. In this study, we aimed to identify potential Escherichia coli GyrB inhibitors from a database of phytoconstituents sourced from Indian medicinal plants. Utilizing virtual screening, we performed a rigorous search to identify compounds with the most promising inhibitory properties against GyrB. Two compounds, namely Zizogenin and Cucurbitacin S, were identified based on their favorable drug likeliness and pharmacokinetic profiles. Employing advanced computational techniques, we analyzed the binding interactions of Zizogenin and Cucurbitacin S with the ATP-binding site of GyrB through molecular docking simulations. Both compounds exhibited robust binding interactions, evidenced by their high docking energy scores. To assess the stability of these interactions, we conducted extensive 100 ns molecular dynamics (MD) simulations, which confirmed the stability of Zizogenin and Cucurbitacin S when bound to GyrB. In conclusion, our study highlights Zizogenin and Cucurbitacin S as promising candidates for potential antibacterial agents targeting GyrB. Experimental validation of these compounds is warranted to further explore their efficacy and potential as novel antibiotics to combat antibiotic-resistant bacteria.Communicated by Ramaswamy H. Sarma.