Search

الملخص: أهداف البحث: داء البلهارسيات هو مرض استوائي مهمل وسبب رئيسي للوفيات في المناطق المتضررة. في الوقت الحاضر، لا يوجد لقاح عملي لمكافحة داء البلهارسيات، مما يضع الاعتماد الكبير على الاستخدام الواسع النطاق لعقار البرازيكوانتيل. يثير الاستخدام الشامل لعقار برازيكوانتيل مخاوف بشأن ظهور المقاومة للأدوية. ونتيجة لذلك، هناك حاجة إلى أهداف علاجية جديدة ومركبات محتملة لمكافحة داء البلهارسيات. طريقة البحث: تم تحسين أربعة وعشرين مشتقا قويا من البرازيكوانتيل من خلال نظرية الكثافة الوظيفية عند مستوى ''ب3ليب/6-31ج''. تم إنشاء نماذج العلاقة الكمية بين الهيكل والنشاط، وتم التحقق من صحتها إحصائيا وتم اختيار المرشح الرئيسي بهدف تطوير المزيد من الخيارات العلاجية مع تحسين الفعالية تجاه داء البلهارسيات. تم تقييم الطاقات البيولوجية وطاقة الارتباط للمركبات المصممة. كما تم إجراء دراسات الديناميكية الجزيئية والتشابه الدوائي والامتصاص والتوزيع والتمثيل الغذائي والإفراز والسمية والكثافة الوظيفية على المركبات المصممة حديثا. النتائج: تم إنشاء خمسة نماذج لعلاقة الهيكل بالنشاط الكمي، من بينها تفوق النموذج 1 بمعلمات التحقق المفضلة، وتم اختياره لتحديد مرشح رئيسي. المعلمات الإحصائية الأخرى للنموذج المختار كانت تتراوح قيم عامل تضخم التباين من 1.242 إلى 1.678 ومعامل التخليط البالغ 0.747. تم تصميم خمسة مركبات جديدة أظهرت أنشطة متوقعة محسنة (تتراوح من 5.081 إلى 7.022)، متجاوزة كلا من الرصاص والبرازيكوانتيل المتوقع البالغ 5.545 .يكشف تحليل محاكاة الديناميكيات الجزيئية عن تقارب الارتباط العالي للمركبات المقترحة تجاه المستقبل المستهدف. تظهر تقييمات الامتصاص والتوزيع والتمثيل الغذائي والإفراز والسمية والتشابه مع الأدوية الالتزام بمعايير ليبينسكي، مما يشير إلى السلامة الدوائية والفموية. كما يشير تحليل نظرية الكثافة الوظيفية إلى مقاومة التغير الإلكتروني أثناء التفاعلات الكيميائية. الاستنتاجات: تظهر المركبات المقترحة خصائص الأدوية المحتملة، مما يشير إلى مدى ملاءمتها لمزيد من البحث لتعزيز خيارات علاج داء البلهارسيات. Abstract: Objectives: Schistosomiasis, a neglected tropical disease, is a leading cause of mortality in affected geographic areas. Currently, because no vaccine for schistosomiasis is available, control measures rely on widespread administration of the drug praziquantel (PZQ). The mass administration of PZQ has prompted concerns regarding the emergence of drug resistance. Therefore, new therapeutic targets and potential compounds are necessary to combat schistosomiasis. Methods: Twenty-four potent derivatives of PZQ were optimized via density functional theory (DFT) at the B3LYP/6-31G∗ level. Quantitative structureactivity relationship (QSAR) models were generated and statistically validated, and a lead candidate was selected to develop therapeutic options with improved efficacy against schistosomiasis. The biological and binding energies of the designed compounds were evaluated. In addition, molecular dynamics; drug-likeness; absorption, distribution, metabolism, excretion, and toxicity (ADMET); and DFT studies were performed on the newly designed compounds. Results: Five QSAR models were generated, among which model 1 had favorable validation parameters (R2train: 0.957, R2adj: 0.941, LOF: 0.101, Q2cv: 0.906, and R2test: 0.783) and was chosen to identify a lead candidate. Other statistical parameters for the chosen model included variance inflation factor values ranging from 1.242 to 1.678, and a Y-scrambling coefficient (cRp2) of 0.747. Five new compounds were designed with improved predicted activity (ranging from 5.081 to 7.022) surpassing those of both the lead compound and PZQ (predicted pEC50 of 5.545). Molecular dynamics simulation revealed high binding affinity of the proposed compounds toward the target receptor. ADMET and drug-likeness assessments indicated adherence to Lipinski's rule of five criteria, thereby suggesting pharmacological and oral safety. In addition, DFT analysis indicated resistance to electronic alteration during chemical reactions. Conclusion: The proposed compounds exhibited potential drug characteristics, thus indicating their suitability for further investigation to enhance schistosomiasis treatment options.

With the progress in two distinct areas of nanotechnology and aptamer identification technologies, the two fields have merged to what is known as aptamer nanotechnology. Aptamers have varying properties in the biomedical field include their small size, non-toxicity, ease of manufacturing, negligible immunogenicity, ability to identify a wide range of targets, and high immobilizing capacity. Nevertheless, aptamers can utilize the distinct characteristics offered by nanomaterials like optical, magnetic, thermal, electronic properties to become more versatile and function as a novel device in diagnostics and therapeutics. This engineered aptamer conjugated nanomaterials, in turn provides a potentially new and unique properties apart from the pre-existing characteristics of aptamer and nanomaterials, where they act to offer wide array of applications in the biomedical field ranging from drug targeting, delivery of drugs, biosensing, bioimaging. This review gives comprehensive insight of the different aptamer conjugated nanomaterials and their utilization in biomedical field. Firstly, it introduces on the aptamer selection methods and roles of nanomaterials offered. Further, different conjugation strategies are explored in addition, the class of aptamer conjugated nanodevices being discussed. Typical biomedical examples and studies specifically, related to drug delivery, biosensing, bioimaging have been presented.

Abstract In recent years, the outbreak of infectious disease caused by Zika Virus (ZIKV) has posed a major threat to global public health, calling for the development of therapeutics to treat ZIKV disease. Several possible druggable targets involved in virus replication have been identified. In search of additional potential inhibitors, we screened 2895 FDA-approved compounds using Non-Structural Protein 5 (NS5) as a target utilizing virtual screening of in-silco methods. The top 28 compounds with the threshold of binding energy −7.2 kcal/mol value were selected and were cross-docked on the three-dimensional structure of NS5 using AutoDock Tools. Of the 2895 compounds screened, five compounds (Ceforanide, Squanavir, Amcinonide, Cefpiramide, and Olmesartan_Medoxomil) ranked highest based on filtering of having the least negative interactions with the NS5 and were selected for Molecular Dynamic Simulations (MDS) studies. Various parameters such as RMSD, RMSF, Rg, SASA, PCA and binding free energy were calculated to validate the binding of compounds to the target, ZIKV-NS5. The binding free energy was found to be −114.53, −182.01, −168.19, −91.16, −122.56, and −150.65 kJ mol−1 for NS5-SFG, NS5-Ceforanide, NS5-Squanavir, NS5-Amcinonide, NS5-Cefpiramide, and NS5-Ol_Me complexes respectively. The binding energy calculations suggested Cefpiramide and Olmesartan_Medoxomil (Ol_Me) as the most stable compounds for binding to NS5, indicating a strong rationale for their use as lead compounds for development of ZIKV inhibitors. As these drugs have been evaluated on pharmacokinetics and pharmacodynamics parameters only, in vitro and in vivo testing and their impact on Zika viral cell culture may suggest their clinical trials on ZIKV patients.

A novel coronavirus (SARS-COV-2) overflow event, with its epicenter point in the Wuhan (China), has risen as the health of the public crisis is of global concern. This started as an episode in the December, (2019), and till the 28th of February, (2020), there have about 83,704 committed cases of the SARS-COV-2 (COVID-19) disease at the global level, including 2,859 deaths. This showed overall cases including 3.41% of the fatality rate. At this point more than 58 nations or regions were affected with SARS-COV-2 (COVID-19) disease. As an important role of the worldwide response to manage and contain this pandemic, significant accentuation was put to create research knowledge in order to manage proof based response to carry the infection. This disease was named as severe respiratory syndrome COVID-19 (SARS-CoV-2), owing to its hereditary similarities with the SARS infection. Individual to-individual transmission of the COVID-19 contamination led to the isolation of the patients that were treated with various types of treatments. Various measures have been executed to decrease the individual to-individual transmission of the SARS-CoV-2, to stop the present outbreak. Unique considerations and many efforts ought to be applied in the populations to decrease the transmission of COVID-19 including health care providers, kids and older individuals. The aims of this review were to highlight the epidemiology, transmission, diagnosis and future instructions of COVID-19 to stop spreading of this lethal disease.

ARR19 (androgen receptor corepressor-19 kDa), a leucine-rich protein whose expression is down-regulated by luteinizing hormone and cAMP, is differentially expressed during the development of Leydig cells and inhibits testicular steroidogenesis by reducing the expression of steroidogenic enzymes. However, the molecular events behind the suppression of testicular steroidogenesis are unknown. In the present study, we demonstrate that ARR19 inhibits the transactivation of orphan nuclear receptor Nur77, which is one of the major transcription factors that regulate the expression of steroidogenic enzyme genes in Leydig cells. ARR19 physically interacts with Nur77 and suppresses Nur77-induced promoter activity of steroidogenic enzyme genes including StAR, P450c17, and 3β-HSD in Leydig cells. Transient transfection and chromatin immunoprecipitation assays revealed that ARR19-mediated reduced expression of steroidogenic enzyme genes was likely due to the interference of SRC-1 recruitment to Nur77 protein on the promoter of steroidogenic enzyme genes. These findings suggest that ARR19 acts as a novel coregulator of Nur77, in turn regulating Nur77-induced testicular steroidogenesis, and may play an important role in the development and function of testicular Leydig cells. [ABSTRACT FROM AUTHOR]