الكهنة والمبشرون بقدوم الرسول الكريم محمد (ص) قبل البعثة

الملخص: بعث الله سبحانه وتعالى سيدنا محمداً (ص) رحمة للناس؛ وليرشدهم إلى طريق الهدى، وإلى تصحيح أمور حياتهم، فهو (ص) خير من أُرسلَ لإتمام هذه الرسالة، ونشر دين الإسلام إلى البشرية؛ إذ وكان الإنسان الوحيد في التاريخ الذي نجح نجاحاً مطلقاً على كلا المستويين الديني والدنيوي، فهو من دعا إلى الاسلام ونشره كواحد من أعظم الديانات، وبعد (14) قرناً من وفاته، فأثره مازال باقياً متجدداً لما له الأثر الأعظم في التاريخ، والعالم. وهدفت الدراسة لاظهار مدى معرفة التنبؤات التي جاءت من خلال الكهنة والمبشرين والذي عرفت من خلال الكتب السماوية التي سبقت مجيء الحبيب المصطفى (ص) واستخدم الباحث المنهج الموضوعي في تسلسل الاحداث التاريخية، وقد توصلت الدراسة الى مجموعة من النتائج اهمها: اكدت الدراسة ان تنبئ العديد من الكهنة والعرافين بقدوم محمد (ص) ولكن كان العالم بانتظاره على مدى طويل فنلاحظ ان الكهنة في العصر الجاهلي قد تحدثوا عن نبي يأتي في المستقبل الا انهم كانت رؤيتهم الى النبيالاكرم القادم رؤي واضحة الى اولى الالباب وهذا مااصبح جليأ في ولادة نبي محمد (ص) والاحداث التي رافقته الى بعثتة فكانت مصداقا لاقوالهم انذاك. الكلمات المفتاحية: الكهنة، البشارة، الرسول، محمد (ص)، البيعثة

Determination of Novel Substrtae Candidates for Protein Kinases to Explore Their Functional Implications in Cancer Theraputics

With the advent of novel technologies and initiatives, increasing numbers of kinases associated with divergent structural features are available. However, their underlying phosphorylation targets and structure-based functional classifications require identifying additional elements. Here, the value of detecting structural relationships of Polo like kinase 1 (PLK1) is reviewed for target identification, cancer therapeutics and development of inhibition strategies. PLK1 is a key player in orchestrating the wide variety of cell-cycle events, ranging from centrosome maturation, mitotic entry, transcriptional control, spindle assembly, mitotic progression, cytokinesis and DNA damage checkpoint recovery. Despite the growing knowledge of PLK1 functional diversity; there have been a limited number of proteins known to be phosphorylated by PLK1. Integration of multiple data sources and techniques is required for high throughput analysis of PLK1 phosphoproteome. Particularly, structural localization of phosphorylation sites is fundamental in ascertaining structure-function relationships and prediction of novel players. To address the multifunctioning of PLK1, focused on molecular structural descriptions, a range of bioinformatics methodologies were devised. Collectively, about 4,521 phosphodependent proteins, sharing similarity to the consensus phosphorylation and polo-box domain (PBD) recognition motifs, have been demonstrated. Subsequent application of filters including similarity index, Gene Ontology enrichment and protein localization resulted in stringent pre-filtering of irrelevant candidates and resulting in the isolation of unique targets with well-defined roles in cell cycle machinery and carcinogenesis. These candidates were further refined structurally using molecular docking and dynamics simulation assays. Overall, identification of these phosphorylation targets has provided the basis of classifying PLK1 cell cycle related functions. PLK1 is known to overexpress in oesophageal (OE) cancer. However, its downstream targets playing unique roles in OE are rare and less informative. The use of collective knowledge has proven to be a promising means in this respect. It is a well established fact that PLK1 directly interacts with tumor suppressor p53 and co-regulated targets prune crosstalk between their functional associations. PLK1 inhibition triggers activation of p53 level in tumor cells, while inactive p53 results in mitotic arrest and DNA damage. To reveal specific PLK1 phosphorylation sites in p53 wild-type and mutant OE cell lines, phosphoproteomics screen was performed whichsuccessfully captured the functional contributions of PLK1 targets. Moreover, by comparative annotations, an unprecedented landscape of phosphorylated motifs was achieved, leading to the distinctiveness of p53 function and prediction of novel biomarkers. In an attempt to narrow down the list of PLK1 targets in oesophageal adenocarcinoma, RNA-sequencing data of four OE patients were integrated with mass spectrometry data of OE cell lines. This strategy extracted two novel phosphorylation targets, small ubiquitin-like modifier (SUMO1) and heat shock protein beta-1 (HSPB1), which were further verified by in vitro phosphorylation assays. Consequently, through Proximity ligation and co-immunoprecipitation assays, it was found that both SUMO1 and HSPB1 stably interact with PLK1. The potential PLK1 binding sites of these targets were analyzed through modeling and docking approaches. In an effort to characterize novel binding signatures of PLK1-PBD, we developed an in vitro next generation peptide phage library screen. Specific peptides were identified in the eluted PBD and control fractions. Subsequent BLAST analysis of PBD consensus sites identified several known and novel mitotic players, implicated in PLK1-dependent pathways. The bound peptides were evaluated at sequence and structure levels to delineate novel interactions and their corresponding binding sites. Based on the evidence that PLK1 expression is elevated in cancer cells, PLK1 serves as a potential therapeutic target for the development of cancer specific drugs. However, all the existing inhibitors either target PLK1-PBD or kinase domain, exclusively. Through integration of ensemble of bioinformatics techniques, bifunctional inhibitors have been predicted which target both domains of PLK1 in parallel. The identified inhibitors were deeply analyzed for their binding pattern and stability through molecular dynamics simulation assays. Overall, these bifunctional inhibitors may be more potent and serve as better therapeutic options, following experimental validation