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Combined Ligand and Structure Based Studies on Modulators of Akt Kinases

Thesis Info

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Author

Noreen Akhtar

Program

PhD

Institute

National University of Sciences & Technology

City

Islamabad

Province

Islamabad

Country

Pakistan

Thesis Completing Year

2019

Thesis Completion Status

Completed

Subject

Computational Science & Engineering

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/11086/1/Noreen%20Akhtar_Comp%20Sci%20%26%20Engg_2019_NUST_PRR.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676725746751

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Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/threonine kinases with three structurally homologous mammalian isoforms, Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ). Akt isoforms emerged as anti-cancer drug targets because of their constitutive hyperactivation in various oncological disorders. However, due to high intra-family similarity within ATP binding region, the development of isoform-selective modulators of Akt represent a challenging endeavor and thus, until now only a handful of compounds were selected for the clinical investigation. Yet none of them could reach the market for routine clinical use due to their off-target toxicity and poor pharmacokinetic properties. Recent reports on achieving isoform selectivity by designing inhibitors against less conserved pleckstrin homology (PH) domain offer the opportunity to reduce the major off-target toxic effects of Akt antagonists. Therefore, in this thesis, combined ligand- and structure-based in silico strategies have been utilized to probe the key structural features for the inhibition of the PH domain of Akt2 which is more commonly overexpressed in solid tumors. Toward this end, various predictive 2DQSAR (two-dimensional quantitative structure-activity relationship) and GridIndependent Molecular Descriptor (GRIND) and pharmacophore models using structurally diverse data set of 111 quinoline analogs have been developed. Our key findings demonstrate that the presence of three hydrogen bond donors (D1-D3) at a molecular distance of ~8.4, 21.6, 16.8 Å between D1–D2, D1–D3 and D2–D3, respectively is important for selective inhibition of PH domain of Akt2. In addition, our docking results indicated a crucial role of Lys30 for the optimal fit of quinoline-type inhibitors within the binding cavity of the Akt2 PH domain. Moreover, the structurebased pharmacophore model exhibited three hydrogen bond acceptors (A1-A3) at a distance of 4.05 Å (A1-A2), 11.58 Å (A2-A3) and 15.33 Å (A1-A3) that are complementary to the molecular distances identified by GRIND which further validate the reliability of our developed models. Additionally, identified hits through pharmacophoric-based virtual screening provided a new arsenal of potentially selective chemical scaffolds which have a broad structural diversity and less chemical similarity to any of the other known Akt2-PH domain inhibitors. Subsequently, selectivity profiling with the help of proteochemometric modeling revealed essential substructures such as Nmethylpent-3-en-2-amine for selective inhibition of Akt1, methylene amine, isoproenylterazol and 2H-tetrazole for Akt2, and formaldehyde hydrazine for the Akt3 selective inhibition. The present work also illustrates the substructure based similarity search of ChemBridge database to identify Akt2-selective hit compounds. In the present study, one of the selected carboxamide-type hit showed 1.2 and 2.1 fold selectivity against Akt2 as compared to Akt1 and Akt3, respectively. Overall, the work described in this thesis could pave the way towards the identification of potential modulators of Akt2 against cell proliferation in cancer with high isoform-selectivity and limited side effects.
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مولانا مودودیؒ اورجماعت اسلامی کیلئے رکاوٹیں

مولانا مودودیؒ کی قائم کردہ مذہبی وسیاسی جماعت آج تک اسلامی نظام کے قیام اوراحیائے اسلام کیلئے کام کرتی چلی آرہی ہےپھرمولانا مودودیؒ نے ۱۹۶۵ء میں کشمیرکی آزادی کیلئے کی جانے والی کوششوں کوجہاد کا درجہ دے دیا ۔ ۱۹۵۳ء میں آپ کوقادیانی مسئلہ کاپمفلٹ لکھنے کے جرم میں موت کی سزادی گئی اورعلما کی گرفتاری پربیان جاری کرنے کے جرم میں سات سال قیدبامشقت کی سزا دی گئی ۔[[1]]مولانا مودودیؒ کی سزا کو بعدمیں عمرقید میں تبدیل کردیاگیا۔آپؒ کو وزیراعظم خواجہ ناظم الدین اورسیکرٹری جنرل چوہدری محمد علی کی مداخلت پر رہاکردیاگیا ۔



[[1]]         مودودی، آئین تفہیم القرآن ،لاہور ،ص۱۸۷

Work Fatigue Determination of Nurses in Hospital of Hasanuddin University

This study aims to determine the effect of body mass index (BMI), sleep patterns, working years, physical workload, mental workload, and work time on work fatigue on nurses at Hasanuddin University Hospital Makassar. This research is a quantitative study with a cross-sectional design with a sample size of 56 people. Sampling using a simple random sampling method. Data collection was carried out by means of a questionnaire. Bodyweight is measured by weight scales, body temperature is measured by microtoice, and physical workload is measured by a pulse oximeter, which is by looking at the pulse of the nurse before and after work. Data analysis in this study used the SPSS program. The results of this study indicate that there is an influence between Body Mass Index (BMI) on work fatigue (p = 0.001), there is an effect of sleep patterns on work fatigue (p = 0.019), there is an effect of tenure on work fatigue (p = 0.017), the relationship between physical workload and work fatigue (p = 0.000), there is an effect of mental workload on work fatigue (p = 0.000) and there is an effect of length of work on work fatigue (p = 0.017). The physical workload is the variable with the greatest influence on work fatigue on nurses at Hasanuddin University Hospital Makassar with Exp. (B) = 14,526. The results of this study concluded that there was a significant influence between the Body Mass Index (BMI), sleep patterns, years of work, physical workload, mental workload, and length of work for nurses at Hasanuddin University Hospital Makassar.

Study of Population Dynamics of Cockroaches Collected from Lahore With Resistance Patterns of Their Isolated Microbial Fauna

Cockroaches are one of the most important pests in urban communities and are risky for human health because they play an important role in transmitting different diseases either mechanically or occasionally biologically. Environmental and sanitary conditions associated with demographic and socio-economic settings of an area could contribute to the prevalence of disease pathogens carried by cockroaches. The present study was aimed to determine taxonomical identification and diversity of cockroaches in hospitals and houses in Lahore, Pakistan and to evaluate the role of cockroaches in transmission of important disease pathogens by using microbial screening of outer surface and digestive tract. Resistance and susceptibility to antimicrobials and disinfectants was also investigated, followed by quantitative and qualitative analysis of total bacterial protein. Four species of cockroaches (P. americana, B. germanica, B. orientalis and B. lateralis) were identified in this study. 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