Nawaz Sharif’s Speeches to the United Nations General Assembly: A Corpus-Based Analysis

Every year heads of different states make their speeches in the general debate of United Nations General Assembly (UNGA). They address national and international issues and suggest measures to resolve them with the help of international community and the United Nations. Muhammad Nawaz Sharif also made speeches in the UNGA. In 2013, he was newly elected prime minister and was enthusiastic to resolve issues with India. There was no internal political pressure on him at that time and the government in India was hostile towards Pakistan. But one year in power and embattled with domestic issues and international pressure, the prime minster approached the issues differently in his 2014 speech. The aim of this paper is to compare his two speeches and see what changes occurred in his stance towards India. The main focus of the analysis is: Who is the addressee of these speeches? How confident did Nawaz feel about the solution of the issues that he raised. The Corpus tool Wmatrix has been used to analyze the data. The results show significant differences in his two speeches with regard to his stance towards India.

Computer-Guided Design and Synthesis of Il-2 Inhibitors As Immunomodulating Agents

Cytokine Interleukin-2 (IL-2) has a prevalent role in the growth, activation, and differentiation o f T-cells. To suppress immune responses associated with organ transplant rejection and other autoimmune diseases, it is important to disrupt the interaction of IL-2 with its receptor system. IL-2 is now emerging as a target in the discovery of novel therapeutics for addressing the problems related to immune system. The main goal of this study was to establish an effective in silico protocol for identification of IL-2 inhibitors. It describes a pharmacophore based virtual screening combined with docking study as a rational strategy for identification of novel IL-2 inhibitors. Structure based pharmacophore model was developed using the crystal structure of IL-2/IL-2Rα (PDB ID: 1Z92) complex. The predictive pharmacophore model consisted of three features, two hydrophobic and one cationic feature with three excluded volumes. The pharmacophore was validated using a training set of thirty known IL-2 inhibitors. Pharmacophore model as a 3D search query was searched against ZINC and MOE database, in order to retrieve new chemical scaffolds that may be potent IL-2 inhibitors. The hits retrieved from this search were filtered based on their RMSD values and pharmacophoric features. Hits that were retained were used in a molecular docking study to find the binding mode and molecular interactions with crucial residues at the active site of the target. Pharmacophore based molecular docking was carried out on virtually screened compounds using 1Z92 as target by MOE software that led to the identification of 15 hits belonging to diverse classes of heterocycles. These hits were further optimized and a library of forty six compounds including 5-6 membered azaheterocycles namely dihydropyrimidines, heteroazepines, pyrazoles and benzimidazoles besides some compounds such as chalcones and Schiff bases, was designed and synthesized. All newly synthesized compounds were characterized by their MS and NMR spectral analysis. IL-2 inhibition studies on the members of the synthesized library led to the identification of novel IL-2 inhibitors with IC 50 values ranging from <2- >50μg/ml using cyclosporine as a standard drug. This entire set of experiments in both dry and wet labs led to a successful designing and synthesis of a variety of compounds as novel scaffolds that may be developed into interesting immunomodulators.