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Computer Aided Drug Design and Analysis of Protein Kinases and Other Related Targets

Thesis Info

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Author

Sajda Ashraf

Program

PhD

Institute

University of Karachi

City

Karachi

Province

Sindh

Country

Pakistan

Thesis Completing Year

2019

Thesis Completion Status

Completed

Subject

Chemistry

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/12438/1/Sajda%20Ashraf_Chem_2019_UoK_PRR.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676725779810

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Current Ph.D. dissertation comprises of five chapters. A brief overview of every chapter is presented to provide an outline of the research contribution which is done in this thesis. Chapter 1 provide details regarding the general introduction of Computer-Aided Drug Discovery (CADD). In particular, it focuses on molecular modeling, Structure-based and Ligand-based drug design methods. Chapter 2 is related to the inhibitory studies of CK2 protein. In this study docking, 3DQSAR and MD simulation are reported with an emphasis on how each method is utilized to gain insight at the molecular level. Alignment obtained from the top-ranked conformation of inhibitors was used for developing the statically significant 3D-QSAR model. A further model was validated through the acceptable extrapolative ability to support both training and test set compounds. Structural changes were observed with the help of MD simulation produced by different substitution on inhibitors. Based on QSAR and MD results some new compounds were also designed. Chapter 3 deals with an effort to identify new pharmacological probes with high specificity for EPAC2 inhibition, using various modern computational tools. Initially, a comprehensive assessment of different scoring function and placement methods was conducted, and effective pharmacophore-based virtual screening protocol was set for the screening of EPAC2 inhibitors. The optimal model with the best six features brought forth and used as a 3D query for virtual screening to retrieve potential inhibitors from Maybridge, Cambridge, and NCI database. The screened compounds were subsequently subjected to molecular docking and 2D-QSAR studies. Finally, 22 top scored compounds with different scaffold having interactions with active site residues were predicted as a lead candidate who may become the starting point in the development of novel and potent EPAC2 inhibitor. Chapter 4 comprise of detailed work on Aurora Kinase B inhibitors. The inhibition of Aurora kinase B is necessary for the treatment of cancerous diseases. By utilizing integrated computational techniques, including 3D-QSAR modeling, pharmacophorebased virtual screening, and MD simulation, we proposed some novel compounds as potential Aurora kinase B inhibitors. Additionally, the highly significant 3D-QSAR model was developed using CoMFA and CoMSIA method. Moreover, the obtained best pharmacophore model was used for virtual screening against a database of over 30 million drugs like molecules which were randomly selected from large commercially available databases, i.e. Chembridge, National Cancer Institute database (NCI), Maybridge and ZINC database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMFA model. Visual inspection, docking calculations, and MD simulation revealed that novel leads established better binding affinities with Aurora kinase B. Chapter 5 deals with the antidiabetic potential of naturally occurring flavonoids. In this study, 9 selected flavonoids compounds were evaluated for their binding affinities with PKA via molecular docking study. According to in silico prediction, these compounds are involved in PKA dependent pathway which was further explored by in vitro mice islets.
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مولاناصبغۃ اﷲ شہید فرنگی محلی

مولانا صبغتہ اﷲ شہید فرنگی محلی
افسوس ہے کہ گذشتہ مہینے ۲۴؍ دسمبر کو مولانا صبغتہ اﷲ صاحب شہید فرنگی محلی نے اتتقال فرمایا مرحوم ایک نامور عالم، لایق مدرس، خوش بیان خطیب، شگفتہ نگار ادیب اور خوش فکر شاعر تھے، ان کی سیرت کی تقریریں خصوصیت کے ساتھ بڑی موثر اور دل آویز ہوتی تھیں، عرصہ تک مدرسہ نظامیہ میں درس و تعلیم کی خدمت انجام دی، ایک زمانہ میں النظامیہ کے نام سے ایک رسالہ بھی نکالا تھا، انجمن خدام کعبہ کے عہدہ دار اور اس کے اخبار خادم الحرمین کے اڈیٹر رہے، خلافت اور ترک موالات کی تحریکوں میں بھی سرگرمی سے حصہ لیا تھا پھر لیگ میں شامل ہوگئے تھے، آداب و اخلاق میں قدیم تہذیب و شائستگی کا نمونہ، بڑے وضعدار خوش مذاق، بذلہ سنج اور علم مجلسی کے ماہر تھے صنع جگت سے بھی ذوق رکھتے تھے، غرض ان کی ذات میں بڑی جامعیت تھی، ان کی وفات سے بہت سی خصوصیات کا خاتمہ ہوگیا، اﷲ تعالیٰ ان کی مغفرت فرمائے۔ (شاہ معین الدین ندوی،جنوری ۱۹۶۵ء)

 

سیرت طیبہ کے تناظر میں پختون خواتین کی موجودہ معاشرت کا تحقیقی جائزہ

Women play a role of paramount importance in the establishment of a distinctive nature of society. Women in Pakhtūn society are regarded with respect and piety. Pakistanis in general and Pakhtūn nation in particular can tolerate monetary losses, owing to their women but they cannot tolerate immoral and disgraceful events attached with their women (mothers, sisters, wives, and daughters) which most often become a reason for the domestic enmities and hostilities. In this article, efforts were made to answer the questions; that whether the different aspects of female lives have been treated according to the teachings of Sīrah or religion is used only as a weapon to suppress them and snatch their rights. The purpose of the study was to investigate the social issues of women from birth related ceremonies, assigning names, training and education, marriage, life after marriage and heredity related issues to their domestic routine issues and how to solve these issues in the light of teachings of the Prophet (P.B.U.H)? Furthermore, suggestions were given to make these solutions more effective and easy to be implemented in our society.

Effect of Li2wo4 and Li3po4 Addition on the Sintering Temperature and Dielectric Properties of Batio3-Based Ceramics

The growing demand for multi-layer ceramic capacitor (MLCCs) in electronic industry has attracted immense research interest due their high capacitance, small size, reliability and excellent high frequency characteristics. Furthermore, a decrease in the sintering temperature of BaTiO3 (BT) based compounds without too much compromise on the dielectric properties is technologically important in the fabrication of MLCCs. The objective of the present study was to investigate the effect of Li3PO4 and Li2WO4 addition on the sintering temperature and dielectric properties of BT-based ceramics for their possible applications in MLCCs. A number of compositions in the (1-x)BaTiO3–xLi3PO4 (x = 0, 0.01, 0.03, 0.05, 0.10) and (1-x)BaTiO3–xLi2WO4 (x = 0, 0.01, 0.05, 0.10) series were prepared via a solid state reaction route and characterized in terms of phase purity, microstructure and electrical properties. Both the additives were found effective in lowering the sintering temperature of BT from ~1350 ºC to ~1150 ºC. X-ray diffraction analysis revealed the formation of tetragonal BT along with BaLiPO4 at x = 0.01-0.05 and another additional secondary LiPO3 phase at x = 0.10 in the case of (1-x)BaTiO3–xLi3PO4. The Li2WO4 added BT samples revealed the formation of tetragonal BT with an additional phase BaWO4 at x = 0.01-0.10. The dielectric constant for Li3PO4 added samples decreased from ~4288 to ~3600, remnant polarization from 6.70 μC/cm2 to 3 μC/cm2 and coercive field from 3.32 kV/cm to 2.5 kV/cm with an increase in x from 0 to 0.05. In the case of Li2WO4 added samples, the dielectric constant decreased from ~4288 to ~1064. The Curie temperature (Tc) peak of Li2WO4 added samples became more diffused and shifted towards room temperature with an increase in x from 0 to 0.10. The IV remnant polarization of Li2WO4 added samples decreased from ~6.70 μC/cm2 to ~2 μC/cm2 while the coercive field increased from ~3.32 kV/cm to ~7.5 kV/cm, when x was increased from 0 to 0.10. Moreover, for the (1-x)BaTiO3–xLi3PO4 (x = 0, 0.01, 0.03, 0.05, 0.10) compositions, the bulk and grain boundary conductivities decreased as x was increased to 0.05, possibly due to a decrease in the grain size. While the activation energy of the grain boundary increased with an increase in x from 0.01 to 0.05 as a consequence of an increase in grain boundary area. Upon further increase in x to 0.10, the observed decrease in the activation energy (grain boundary) indicated a decrease in the concentration of grain boundaries and an increase in grain size of the secondary phases, for x = 0.10. The bulk and grain boundary conductivities of (1-x)BaTiO3–xLi2WO4 compositions also decreased with increasing x. The activation energy for the bulk decreased due to Li2WO4 addition (x = 0.01) and then increased upon further increase in the concentration of Li2WO4 (up to x = 0.05). On the other hand, activation energy for the grain boundary, initially increased with the addition of Li2WO4 (at x = 0.01) and decreased upon further increase in the concentration of the additive to x = 0.10. This may be due to the consequent increase in the concentration of the secondary phase (BaWO4) as well as a small increase in the grain size. These two electro-active regions (i.e., grain and grain boundary) having different thermal activation energies suggested two different transport mechanisms in the (1-x)BaTiO3–xLi2WO4 (where x = 0, 0.01, 0.05, and 0.10) ceramics investigated in the present study. V In conclusion, these results suggest that Li3PO4 and Li2WO4 were effective in lowering the sintering temperature for BT–based ceramics and may be considered as potential candidate materials for the fabrication of MLCCs.