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

Thesis Info

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Author

Kalsoom, Saima

Program

PhD

Institute

Quaid-I-Azam University

City

Islamabad

Province

Islamabad.

Country

Pakistan

Thesis Completing Year

2016

Thesis Completion Status

Completed

Subject

Chemistry

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/2933/1/Saima_Kalsoom_organic_Chemistry_2016_HSR_QAU_22.12.2016.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676725780601

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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.
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ڈاکٹر محمد ایوب قادری

ڈاکٹر محمد ایوب قادری
پاکستان وبھارت کے علمی اور دینی حلقوں میں یہ خبر بڑے رنج وغم کے ساتھ سنی گئی کہ۲۵/نومبر۱۹۸۳ء کوپاکستان کے ایک نامور ادیب،مصنف اور مؤرخ ڈاکٹر محمد ایوب قادری کراچی میں ٹریفک کے ایک حادثے میں جاں بحق ہوگئے۔ وفات کے وقت ان کی عمر۵۶برس کے لگ بھگ تھی۔
قادری صاحب روہیلکھنڈ کے مشہور تاریخی قصبے آنولہ کے رہنے والے تھے۔ان کی ابتدائی تعلیم بدایوں اوربریلی میں ہوئی۔تقسیم ملک کے بعد موصوف کراچی چلے گئے۔کراچی جاکر انھوں نے اپنی تعلیم جاری رکھی اوربالآخر اردو کالج کراچی میں شعبۂ اردو میں لیکچرار مقرر ہوئے اور محنت،لگن اورخلوص کی بدولت آخر میں شعبۂ اردو کے صدر بن گئے۔
قادری صاحب کوروہیلکھنڈ کی تاریخ، رجال اور اماکن پربڑی دسترس تھی۔اس کے علاوہ۱۸۵۷ء کی جنگِ آزادی کے ہیرو ان کی تحقیق کا محور تھے۔ انھوں نے مخدوم جہانیاںؒ کاایک تذکرہ لکھا اورمآثرالامراء کااردو میں ترجمہ کیا۔ مرحوم نے مجلہ اردو کالج کراچی کے کئی شاندار نمبرنکالے۔پاکستان اوربھارت کے علمی وادبی رسائل میں ان کے مضامین اکثرچھپتے رہتے تھے۔
۲۵/نومبر کی شام کو موصوف اپنے گھرواقع شمالی ناظم آباد سے چلے۔ابھی انھوں نے بمشکل سو سواسوگز کا فاصلہ طے کیاہوگا کہ ایک ویگن ان کے سرسے ٹکرا گئی اورموصوف موقع پرہی جان بحق ہوگئے۔
یہ بھی عجیب بات ہے کہ ان کے ایک حقیقی بھائی ابومعاویہ نعمت اﷲ قادری بھی ۲/فروری۱۹۸۱ء کولیاقت آباد کراچی میں ٹریفک کے ایک ایسے ہی حادثے میں جاں بحق ہوئے تھے۔ابومعاویہ کودیکھ کرقرنِ اوّل کے مسلمانوں کی یادتازہ ہوتی تھی۔انھوں نے اس مادی دور میں اپنے تمام بچوں کودینی مدارس میں تعلیم دلوائی۔
یہ دونوں بھائی بڑی خوبیوں کے مالک اور اعلیٰ انسانی اوصاف سے متصف تھے۔اﷲ تعالیٰ ان کومغفرت وبخشش کی نعمتوں سے سرفراز فرمائے۔
[مارچ۱۹۸۴ء]

 

The Analytical Study of Well Thought-Out Legitimate Pakhtun’s Trends Regarding Marriage Binding Shariah Perspective

Indeed, nobody can deny the role and importance of women in any peaceful society. Their contribution is not only essential to enhance the living standard but also they are life blood of prosperity and beauty of this universe. In each & every field of life their need is felt but regrettably, it is not realized by all that how much women have experienced discrimination and deprivation of their rights and freedom. Many of restrictions and limitations faced by them are due to culture and tradition. Although women play an important role in the development and success of men, but do not get any reward for their allegiance, loyalty and devotion.  Islam acknowledged equality of women with men in a great way. In Islam women get a praiseworthy and admirable position which no religion ever gave them. Islam defined their duties and ordered to treat them equally but in spite of all that the woman of today’s Muslim world in general and Pakhtun society in particular is not entertaining their rights and status. This study specifically focusses on highlighting one of the Pakhtun customs and its aspects that badly violate the religious teachings regarding the Women marriage Status and there will also be some recommendations in order to eradicate these unlawful trends from society as to empower the women in real sense.

Emotional Labor, Employees Affective States and Job Satisfaction: Role of Supervisory Support

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