سرکاری عہدید اران کی تقررری، نگرانی اور محاسبہ عہد خلفائے راشدین کے تناظر میں

The period of the rightly guided caliphate is the best role model after the time of the Prophet of Islām, Muḥammad (S. A. W). The rightly guided caliphs crafted the best honest governing mechanism. They understood their commitment with their Lord, Allāh, and the people. They took up the responsibility for providing for the basic needs of their people, like food, shelter, education, peace, stipends of children, married and unmarried persons, social security and justice, etc. The caliphs would appoint the tax collectors, governors and other government officials on the basis of merit: their honesty, qualifications, experience, physical fitness, etc. Further, they, at the time of their appointment, would advise their officials in an open gathering to better use their abilities, resources and powers for the welfare of the masses. Moreover, the government prepared a list of the assets and the properties of their government officials at the time of their appointments. It they found, later, significant increase in the assets, it was investigated and asked for an explanation. If the officials failed to justify the means of the increase in their assets, the additional assets and properties were confiscated by government. In this research study, the author highlights the measures adopted by the rightly guided Caliphs to ensure honest conduct of affairs by the appointed officials of the government.

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.