1,720,980 research outputs found
Design of a senolytic proteolysis targeting chimera against the B-cell lymphoma – extra large protein using in silico approaches
No full textDissertation (MSc (Chemical Pathology))--University of Pretoria, 2020.Senescent cells have been linked to age-related diseases and frailty. Their pathogenic effects are mediated by a group of cellular secretions called the senescence-associated secretory phenotype (SASP). Removal of senescent cells has been associated with the delay of the onset of age-related diseases as well as improved physical function. Senescent cells have upregulated pro-survival pathways which confer resistance to apoptosis. The anti-apoptotic BCLXL (B-cell lymphoma-extra large) protein is involved in the survival of senescent cells. Inhibition of BCLXL’s activity has been found to induce apoptosis in senescent human umbilical vein endothelial cells (HUVECs). The von Hippel-Lindau tumor suppressor protein (pVHL) is the substrate recognition subunit of an E3 ubiquitin ligase. The pVHL protein binds to substrate proteins, recruiting them to the E3 ligase for ubiquitination which will result in their degradation. A Proteolysis Targeting Chimera (PROTAC), is a bivalent molecule that promotes interaction between an arbitrary protein target and an E3 substrate recognition subunit. A PROTAC, therefore, forces the ubiquitination and subsequent degradation of a target protein.
Computational methods were used to design PROTACs capable of recruiting BCLXL to the pVHL protein to trigger its degradation and therefore specifically induce apoptosis in senescent HUVECs. The techniques used included pharmacophore-based screening, structural screening, molecular docking and molecular dynamics (MD) simulation. A PROTAP (Proteolysis Targeting Peptide) targeting the same proteins was obtained from literature and recreated in silico to serve as a comparison and proof of concept. The structure of a PROTAC that interacted with pVHL and BRD4 was obtained from the PDB as an additional comparison.
MD simulations were run on ligand-bound BCLXL and pVHL proteins, consequently relatively stable conformations were identified and five pharmacophore models for each protein were developed based on different structures. The BCLXL pharmacophores placed more importance on aromatic rings while the pVHL pharmacophores preferred hydrogen bond donors and acceptors. Pharmacophores were validated by decoy set validation, using BEDROC, accuracy, Güner-Henry score and area under curve as metrics, yielding barely passable results. A starting library of 2 million molecules from the Mcule database was screened, identifying 33005 and 221481 hits for BCLXL and pVHL respectively. Structural screening and molecular docking were used to search
for molecules with good binding characteristics to BCLXL and pVHL, retaining 33 and 216 molecules respectively. Two potential BCLXL ligands and two potential pVHL ligand were joined in different combinations with different glycine linker lengths, yielding eight potential PROTACs. Ternary protein-PROTAC complexes were assembled and used in 100 ns long MD simulations. From the MD trajectories, the RMSD of the proteins and PROTACs, as well as the number of bonds/interactions between them, were examined. Comparisons were made to the RMSD and interactions of the reference PROTAC and PROTAP. Three attractive PROTACs were identified, with one having superior ADMET properties. The binding energy calculations did not find fault with any of the three candidate PROTACs. While there is currently no satisfactory way to evaluate the performance of a PROTAC, the procedures employed identified molecules with the potential to act as a PROTAC.Chemical PathologyMSc (Chemical Pathology)UnrestrictedFaculty of Humanitie
Performance and financial analysis of Shanin Group
Get PDFThis internship report is submitted in a partial fulfillment of the requirements for the degree of Master of Business Administration, 2015.Cataloged from PDF version of Internship report.Includes bibliographical references (page 34-35).Md. Ataul IslamM. Business Administration
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Structural requirements for potential HIV-integrase inhibitors identified using pharmacophore-based virtual screening and molecular dynamics studies
Get PDFAcquired immunodeficiency syndrome (AIDS) is a life-threatening disease which is a collection of symptoms and infections
caused by a retrovirus, human immunodeficiency virus (HIV). There is currently no curative treatment and therapy is
reliant on the use of existing anti-retroviral drugs. Pharmacoinformatics approaches have already proven their pivotal role
in the pharmaceutical industry for lead identification and optimization. In the current study, we analysed the binding
preferences and inhibitory activity of HIV-integrase inhibitors using pharmacoinformatics. A set of 30 compounds were
selected as the training set of a total 540 molecules for pharmacophore model generation. The final model was validated
by statistical parameters and further used for virtual screening. The best mapped model (R = 0.940, rmsd = 2.847, Q2 =
0.912, se = 0.498, R2
pred = 0.847 and r2
m (test) = 0.636) explained that two hydrogen bond acceptor and one aromatic ring
features were crucial for the inhibition of HIV-integrase. From virtual screening, initial hits were sorted using a number of
parameters and finally two compounds were proposed as promising HIV-integrase inhibitors. Drug-likeness properties of
the final screened compounds were compared to FDA approved HIV-integrase inhibitors. HIV-integrase structure in
complex with the most active and final screened compounds were subjected to 50ns molecular dynamics (MD) simulation
studies to check comparative stability of the complexes. The study suggested that the screened compounds might be
promising HIV-integrase inhibitors. The new chemical entities obtained from the NCI database will be subjected to
experimental studies to confirm potential inhibition of HIV integrase.University of Pretoria Vice Chancellor’s post-doctoral fellowship and National Research Foundation (NRF), South Africa.http://www.rsc.orgmolecularbiosystems2017-01-31hb2016Chemical Patholog
Pharmacoinformatics-based identification of chemically active molecules against Ebola virus
Get PDFEbola is a dangerous virus transmitted by animals and humans and to date there is no curable agent for such a deadly infectious disease. In this study, pharmacoinformatics-based methods were adopted to find effective novel chemical entities against Ebola virus. A well predictive and statistical robust pharmacophore model was developed from known Ebola virus inhibitors collected from the literature. The model explained the significance of each of hydrogen bond acceptor and donor, and two hydrophobic regions for activity. The National Cancer Institute and Asinex (Antiviral library) databases were screened using the final validated pharmacophore model. Initial hits were further screened with a set of criteria and finally eight molecules from both databases were proposed as promising anti Ebola agents. Further molecular docking and molecular dynamics studies were carried out and it was found that the proposed molecules possessed capability to interact with amino residues of Ebola protein as well as retaining equilibrium of protein-ligand systems. Finally, the binding energies were calculated using molecular mechanics Poisson–Boltzmann surface area approach and all proposed molecules showed strong binding affinity towards the Ebola protein receptor.The National Research Foundation (NRF), South Africa Innovation post-doctoral fellow-ship scheme.http://:www.tandfonline.com/toc/tbsd20hj2020Chemical Patholog
Simplified molecular input line entry system-based descriptors in QSAR modeling for HIV-protease inhibitors
Get PDFSimplified molecular input line entry system (SMILES) descriptor based quantitative structure–activity relationship
(QSAR) study was performed on a set of HIV-protease inhibitors to explore the structural functionalities for
inhibition of the HIV-protease. For this purpose a set of HIV-inhibitors was collected from the literature along
with their inhibitory constants. Monte Carlo optimization-based CORAL software was used for QSAR model
development. Firstly, the dataset was divided into three random splits and secondly each split was divided
into training, calibration, test and validation sets. A training set was used for model development whereas the
rest of the sets were used to assess the quality of the developed models. QSAR models were developed with
and without considering the influence of cyclic rings toward the inhibitory activity. Statistical quality of QSAR
models developed from all splits was very good and fulfilled the criteria. The values of R2, Q2, s, R2
pred and r2
m
explained that selected models are robust in nature and efficient enough to predict the inhibitory activity of
the molecules outside of the training set. Statistical parameters also suggested that the presence of cyclic rings
have a crucial impact on inhibitory activity. The molecular fragmentswere found to be important for the increase
or decrease of the inhibitory activity which explained that models have mechanistic interpretation. This ligandbased
QSAR study can provide clear directions to design and modulate potential HIV-protease inhibitors.The University of Pretoria
Vice Chancellor's post-doctoral fellowship and the National Research
Foundation (NRF), South Africa Innovation post-doctoral fellowship
schemes.http://www.elsevier.com/locate/chemolab2017-04-30hb2016Chemical Patholog
Exploration of the structural requirements of HIV-protease inhibitors using pharmacophore, virtual screening and molecular docking approaches for lead identification
Get PDFPlease abstract in the article.The University of Pretoria Vice Chancellor's post-doctoral fellowship scheme.http://www.elsevier.com/locate/JMGMhj201
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