569 research outputs found
Oligomeric states of an Influenza-encoded PB1-F2 viroporin
No full text<p>The dataset contains input files to run all simuations and analyses.</p>
Rational Design of Acridine-Based Ligands with Selectivity for Human Telomeric Quadruplexes
No full textStructure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA. Selectivity is a result of the dimensions of the triazole-acridine compounds; and in particular the separation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization
Structural Insights into the Quadruplex-Duplex 3 ' Interface Formed from a Telomeric Repeat: A Potential Molecular Target
No full textWe report here on an X-ray crystallographic and molecular modeling investigation into the complex 3′ interface formed between putative parallel stranded G-quadruplexes and a duplex DNA sequence constructed from the human telomeric repeat sequence TTAGGG. Our crystallographic approach provides a detailed snapshot of a telomeric 3′ quadruplex–duplex junction: a junction that appears to have the potential to form a unique molecular target for small molecule binding and interference with telomere-related functions. This unique target is particularly relevant as current high-affinity compounds that bind putative G-quadruplex forming sequences only rarely have a high degree of selectivity for a particular quadruplex. Here DNA junctions were assembled using different putative quadruplex-forming scaffolds linked at the 3′ end to a telomeric duplex sequence and annealed to a complementary strand. We successfully generated a series of G-quadruplex–duplex containing crystals, both alone and in the presence of ligands. The structures demonstrate the formation of a parallel folded G-quadruplex and a B-form duplex DNA stacked coaxially. Most strikingly, structural data reveals the consistent formation of a TAT triad platform between the two motifs. This triad allows for a continuous stack of bases to link the quadruplex motif with the duplex region. For these crystal structures formed in the absence of ligands, the TAT triad interface occludes ligand binding at the 3′ quadruplex–duplex interface, in agreement with in silico docking predictions. However, with the rearrangement of a single nucleotide, a stable pocket can be produced, thus providing an opportunity for the binding of selective molecules at the interface
New anti-HIV aptamers based on tetra-end-linked DNA G-quadruplexes: effect of the base sequence on anti-HIV activity.
No full textThis communication reports on the synthesis and biophysical, biological and SAR studies of a small library of new anti-HIV aptamers based on the tetra-end-linked G-quadruplex structure. The new aptamers showed EC(50) values against HIV-1 in the range of 0.04-0.15 µM as well as affinities for the HIV-1 gp120 envelope in the same order of magnitud
Interaction of azatrux with the G-quadruplex parallel fold: biophysical insight into the binding propietes to address drug design
No full textIn vivo investigation of (2-hydroxypropyl)-β-cyclodextrin-based formulation of spironolactone in aqueous solution for paediatric use
No full textSpironolactone (SPL), a potent anti-aldosterone steroidal drug used to treat several diseases in paediatric patients (e.g., hypertension, primary aldosteronism, Bartter’s syndrome, and congestive heart failure), is not available in child-friendly dosage forms, and spironolactone liquids have been reported to be unpalatable. Aiming to enhance SPL solubility in aqueous solution and overcome palatability, herein, the effects of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CyD) were thoroughly investigated on solubilisation in water and on masking the unpleasant taste of SPL in vivo. Although the complexation of SPL with HP-β-CyD was demonstrated through phase solubility studies, Job’s plot, NMR and computational docking studies, our in vivo tests did not show significant effects on taste aversion. Our findings, on the one hand, suggest that the formation of an inclusion complex of SPL with HP-β-CyD itself is not necessarily a good indicator for an acceptable degree of palatability, whereas, on the other hand, they constitute the basis for investigating other cyclodextrin-based formulations of the poorly water-soluble steroidal drug, including solid dosage forms, such as spray-dried powders and orodispersible tablets
Politics and Exhaustion — with Asad Haider
No full textTheorist and author Asad Haider joins Below the Radar to discuss questions he explores in his book, Mistaken Identity: Race and Class in the Age of Trump. Asad discusses how class dynamics cannot be separated from identity-driven movements. As well, he explores ideas of political exhaustion in the tradition of political theorists such as Sylvain Lazarus and Alain Badiou. In this interview, Asad interrogates the role of identity in politics and how it has been taken up in discourse — complicating the relationship between race and class in a context that has been defined by capital interests. Asad and Am discuss theoretical questions around frameworks for political organizing and solidarity across movements. He also speaks to our current moment as one of political exhaustion, where it\u27s difficult to mobilize transformative political change
Dynamic structural clustering of Class D β-Lactamases using Molecular simulations and Deep Learning
No full textClass D β-lactamases (DBLs) have gained clinical significance as major contributors to antimicrobial resistance, particularly through carbapenem hydrolysis. While their structural flexibility is increasingly recognized as central to their activity, existing studies of DBL dynamics are fragmented: they focus on individual enzymes, employ inconsistent residue numbering, and thus remain difficult to compare.
This thesis addresses these challenges in three stages. First, a literature consistent annotation framework is introduced. Using OXA-48 as a reference, the SAND (Structural Alignment-based Numbering of DBLs) scheme is developed together with a consensus secondary structure annotation, enabling homologous residues and elements to be consistently identified across the family. This framework resolves inconsistencies in the literature, supports reproducible analyses, and provides a resource for both experimental researchers and AI-based text/data mining tools.
Second, a comparative dynamics study is conducted with the aim of filling the gap of dynamic knowledge among different OXAs and identifying measurable dynamical properties that can be linked to substrate profiles and functional phenotypes of DBLs. Enhanced sampling through adaptive bandit molecular dynamics simulations is used to explore conformational landscapes across representative enzymes, revealing conserved motifs and subfamily-specific differences in loop flexibility and hydrophobic bridge formation.
Finally, deep learning is applied to analyze these large-scale simulations. Convolutional variational autoencoders were trained on inter-residue distance matrices, and the resulting latent representations were projected into low-dimensional spaces. This approach enabled the detection and interpretation of clustering patterns corresponding to metastable conformational states, which were mapped back to structural and functional determinants of substrate specificity.
By integrating structural standardization, comparative dynamics, and deep learning–based interpretation, this thesis establishes a coherent framework linking sequence, structure, dynamics, and function in DBLs. The results consolidate fragmented knowledge, provide mechanistic insights into functional variability, and offer a foundation for rational inhibitor design
Pioneers of Library Movement in Pakistan
No full textThe paper aims to describe in brief the contribution of seven leaders of Pakistan librarianship, viz. K.B. Khalifa M. Asadullah, Prof. Dr. Abdul Moid, Dr. Abdus Subuh Qasimi, Muhammad Shafi, Fazal Elahi, Khawaja Nur Elahi and S. V. Hussain. The early library developments are given for better understanding of the role of these leaders
A critical analysis of Persian Poetry of Shah Turab Ali Qalandar
No full text<p>volume = {1}, number = {1}, author = {Zunnoorain Haider Alavi}, title = {A critical analysis of Persian Poetry of Shah Turab Ali Qalandar}, publisher = {Saurabh Chandra}, journal = {SOCRATES}, ISSN 2347-6869 year = {2013}</p
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