Contributing to the Study of Enzymatic and Chemical Glycosyl Transfer Through the Observation and Mimicry of Glycosyl Cations

Synthesis ◽  
2020 ◽  
Author(s):  
Yves Blériot
Keyword(s):  
Structural Diversity ◽  
Ionic Species ◽  
Glycosidic Bond ◽  
Chemical Probes ◽  
Important Data ◽  
Ring Contraction ◽  
Innovative Strategies ◽  
Processing Enzymes ◽  
Glycosylation Reaction ◽  
Selection Of

AbstractThis account describes our efforts dedicated to: 1) the design of glycomimetics aimed at targeting therapeutically relevant carbohydrate processing enzymes, and 2) the observation, characterization, and exploitation of glycosyl cations as a tool for studying the glycosylation reaction. These findings have brought important data regarding this key ionic species as well as innovative strategies to access iminosugars of interest.1 Introduction2 The Glycosyl Cation, A Central Species in Glycosciences2.1 A Selection of the Strategies Developed so far to Gain Insights into Glycosyl Cations Structure2.2 When Superacids Meet Carbohydrates3 Chemical Probes to Gain Insights into the Pseudorotational Itinerary of Glycosides During Glycosidic Bond Hydrolysis3.1 Conformationally Locked Glycosides3.1.1 The Xylopyranose Case3.1.2 The Mannopyranose Case3.2 Conformationally Flexible Iminosugars3.2.1 Nojirimycin Ring Homologues3.2.2 Noeuromycin Ring Homologues3.2.3 Seven-Membered Iminosugar C-Glycosides4 N-Acetyl-d-glucosamine Mimics5 Ring Contraction: A Useful Tool to Increase Iminosugar’s Structural Diversity6 Regioselective Deprotection of Iminosugar C-Glycosides to Introduce Diversity at C2 Position7 Conclusion

Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain

2020 ◽  
Author(s):  
Luke Adams ◽  
Lorna E. Wilkinson-White ◽  
Menachem J. Gunzburg ◽  
Stephen J. Headey ◽  
Martin J. Scanlon ◽  
...  
Keyword(s):  
Binding Site ◽  
Systematic Approach ◽  
Structural Information ◽  
Peptide Binding ◽  
Chemical Diversity ◽  
Chemical Probes ◽  
Protein Targets ◽  
Structure Activity ◽  
Peptide Binding Site ◽  
Selection Of

The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity >30-fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.<br>

From classrooms to Centres: Mary and David Medd’s contribution to postwar school design in Britain

2020 ◽  
Vol 24 (3) ◽  
pp. 251-264
Author(s):  
Paula Lacomba Montes ◽  
Alejandro Campos Uribe
Keyword(s):  
Great Britain ◽  
Design Process ◽  
School Design ◽  
Ministry Of Education ◽  
Learning Spaces ◽  
Close Collaboration ◽  
Innovative Strategies ◽  
Whole Process ◽  
Conventional School ◽  
Selection Of

This paper reports on the primary school design processes carried out around the 1940s in the County of Hertfordshire in Great Britain, which later evolved into innovative strategies developed by Mary and David Medd in the Ministry of Education from the late 1950s. The whole process, undertaken during more than three decades, reveals a way of breaking with the traditional spatial conception of a school. The survey of the period covered has allowed an in-depth understanding of how learning spaces could be transformed by challenging the conventional school model of closed rooms, suggesting a new way of understanding learning spaces as a group of Centres rather than classrooms. Historians have thoroughly shown the ample scope of this process, which involved many professionals, fostering a true cross-disciplinary endeavour where the curriculum and the learning spaces were developed in close collaboration. A selection of schools built in the county has been used to typologically analyse how architectural changes began to arise and later flourished at the Ministry of Education. The Medds had indeed a significant role through the development of a design process known as the Built-in variety and the Planning Ingredients. A couple of examples will clarify some of these strategies, revealing how the design of educational space could successfully respond to an active way of learning.

Volatility of Financial Metrics: Important Data for Contingent Consideration Valuations

2021 ◽  
Vol 40 (3) ◽  
pp. 80-96
Author(s):  
Vicentiu Covrig ◽  
Daniel McConaughy ◽  
Adam Newman ◽  
Pavan Kumar Nadiminti ◽  
Mary Ann K. Travers
Keyword(s):  
Growth Rate ◽  
Statistical Analysis ◽  
Firm Size ◽  
Common Belief ◽  
Net Income ◽  
Important Data ◽  
Business Valuation ◽  
Financial Metrics ◽  
Detailed Statistical Analysis ◽  
Selection Of

This article presents the first detailed statistical analysis of the volatilities of various commonly encountered financial metrics used in contingent consideration (and earn-out) agreements. The valuation of contingent consideration using an option-based methodology and non-equity volatilities is becoming more common in business valuation. We provide clear evidence that the volatility of five financial metrics—revenue; earnings before interest, taxes, depreciation, and amortization (EBITDA); EBIT, net income, and total assets—is strongly, negatively related to firm size and profitability. However, contrary to common belief, the volatility of these metrics is not related to a firm's financial leverage. We also calculated the volatilities using four different methodologies that are employed in practice. Although no theory guides the selection of methodologies, based upon our work, we have found that the year-over-year growth rate, using a quarterly frequency, provides the most reasonable results.

Innovative Strategies for Lipid-Based Drug Delivery

2018 ◽  
pp. 60-84 ◽  
Author(s):  
Navneet Sharma ◽  
Sabna Kotta ◽  
Mohd Aleem ◽  
Shubham Singh ◽  
Rakesh Kumar Sharma
Keyword(s):  
Drug Delivery ◽  
Drug Absorption ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Water Soluble ◽  
Absorption Process ◽  
Innovative Strategies ◽  
The Poor ◽  
Water Soluble Drugs ◽  
Selection Of

In the last decade, there has been a mounting concern in lipid-based formulations to deliver water-soluble drugs. Lipid-based drug delivery systems are one of the budding and promising technologies designed to tackle the poor bioavailability problems. This chapter stresses the different mechanisms of lipophilic drug absorption along with its advantages and limitations. It points out the different mechanisms of how lipid-based excipients and the different formulations interact with the absorption process. This review provides a comprehensive summary about the lipid formulation classification scheme (LFCS), a guide for the selection of appropriate formulation and commonly used excipients for lipid-based formulations, along with the important factors to be considered in formulation design and excipient selection. This review also focuses on the formulation of solid lipid-based formulations, important evaluation aspects, and commercial formulations available for the purpose.

Room-Temperature Ceramic Nanocoating Using Nanosheet Deposition Technique

2013 ◽  
Vol 2013 (CICMT) ◽  
pp. 000014-000018 ◽  
Author(s):  
M. Osada ◽  
T. Sasaki
Keyword(s):  
Room Temperature ◽  
Organic Molecules ◽  
Structural Diversity ◽  
Layer By Layer ◽  
Precise Control ◽  
Langmuir Blodgett ◽  
Wide Range ◽  
Potential Applications ◽  
Layer Assembly ◽  
Selection Of

We present a novel procedure for ceramic nanocoating using oxide nanosheet as a building block. A variety of oxide nanosheets (such as Ti1−δO2, MnO2 and perovsites) were synthesized by delaminating appropriate layered precursors into their molecular single sheets. These nanosheets are exceptionally rich in both structural diversity and electronic properties, with potential applications including conductors, semiconductors, insulators, and ferromagnets. Another attractive aspect is that nanosheets can be organized into various nanoarchitectures by applying solution-based synthetic techniques involving electrostatic layer-by-layer assembly and Langmuir-Blodgett deposition. It is even possible to tailor superlattice assemblies, incorporating into the nanosheet galleries with a wide range of materials such as organic molecules, polymers, and inorganic/metal nanoparticles. Sophisticated functionalities or paper-like devices can be designed through the selection of nanosheets and combining materials, and precise control over their arrangement at the molecular scale.

The Application of Multi-Axial Warp Knitted Fabrics in Wind Turbine Blade

2011 ◽  
Vol 295-297 ◽  
pp. 46-50 ◽  
Author(s):  
Zhi Yun Wu ◽  
Le Tie
Keyword(s):  
Wind Turbine ◽  
Turbine Blade ◽  
Fossil Fuels ◽  
Structural Diversity ◽  
Wind Turbine Blade ◽  
Molding Process ◽  
Knitted Fabrics ◽  
Comprehensive Performance ◽  
Wind Resources ◽  
Selection Of

With the consumption of fossil fuels and their serious impact on the environment, countries in the world are looking to the development of wind resources and the selection of material and the molding process in wind turbine blade have also put higher requirements. Multi-axial warp knitted fabrics become the good carrier of wind turbine blade with its structural diversity, comprehensive performance, good formability and permeability, etc.

Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain

2020 ◽  
Author(s):  
Luke Adams ◽  
Lorna E. Wilkinson-White ◽  
Menachem J. Gunzburg ◽  
Stephen J. Headey ◽  
Martin J. Scanlon ◽  
...  
Keyword(s):  
Binding Site ◽  
Systematic Approach ◽  
Structural Information ◽  
Peptide Binding ◽  
Chemical Diversity ◽  
Chemical Probes ◽  
Protein Targets ◽  
Structure Activity ◽  
Peptide Binding Site ◽  
Selection Of

The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity >30-fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.<br>

Cyclodextrin Inclusion of Medicinal Compounds for Enhancement of their Physicochemical and Biopharmaceutical Properties

2019 ◽  
Vol 19 (25) ◽  
pp. 2357-2370 ◽  
Author(s):  
Mino R. Caira
Keyword(s):  
Drug Discovery ◽  
Inclusion Complexation ◽  
Structural Diversity ◽  
Attrition Rate ◽  
Cyclodextrin Inclusion ◽  
Biopharmaceutical Properties ◽  
Fine Tune ◽  
Early Drug ◽  
Selection Of

Owing to their wide structural diversity and unique complexing properties, cyclodextrins (CDs) find manifold applications in drug discovery and development. The focus of this mini-review is on their uses as ‘enabling excipients’ both in the context of early drug discovery and in subsequent optimisation of drug performance. Features highlighted here include descriptions of the structures of CDs, synthetic derivatisation to fine-tune their properties, the nature of inclusion complexation of drugs within the CD cavity, methodology for the study of free and complexed hosts in the solid state and in solution, the inherent pharmacological activity of several CDs and its utility, novel CD-based drug delivery systems, and the role of CDs in drug discovery and optimisation. Illustrative examples are generally based on research reported during the last two decades. Application of CDs to the optimisation of the performance of established drugs is commonplace, but there are many opportunities for the intervention of CDs during the early stages of drug discovery, which could guide the selection of suitable candidates for development, thereby contributing to reducing the attrition rate of new molecular entities.

scholarly journals A new method for the selection of protein interactions in mammalian cells

2000 ◽  
Vol 348 (3) ◽  
pp. 585-590 ◽  
Author(s):  
Eileen ROJO-NIERSBACH ◽  
Debra MORLEY ◽  
Stephanie HECK ◽  
Norbert LEHMING
Keyword(s):  
Protein Interactions ◽  
Mammalian Cells ◽  
Homo Sapiens ◽  
Fibroblast Cell ◽  
New Method ◽  
Suitable Alternative ◽  
Processing Enzymes ◽  
Selection Of

In the present study we present a new method that allows for the selection of protein interactions in mammalian cells. We have used this system to verify two interactions previously characterized in vitro. (1) The interaction between human TATA-binding protein 1 and nuclear factor ĸB and (2) the association of Homo sapiens nuclear autoantigen SP100B with human heterochromatin protein 1α, a protein implicated in chromatin remodelling. We observe for the first time that these interactions also occur in vivo. One protein was fused to the N-terminal half of ubiquitin, while the interacting partner was fused to the C-terminal half of ubiquitin, that was itself linked to guanine phosphoryltransferase 2 (gpt2) modified to begin with an arginine residue. Upon interaction of both proteins, ubiquitin is reconstituted, and its association with the Rgpt2 reporter is subsequently cleaved off by ubiquitin-processing enzymes. The presence of arginine in the Rgpt2 gene product leads to the degradation of the product by the N-end rule pathway. In the human fibroblast cell line HT1080HPRT- (that is deficient in the enzyme for hypoxanthine-guanine phosphoribosyltransferase) cells in which interaction between both proteins of interest occurs can then be selected for by hypoxanthine/aminopterin/thymine medium and counterselected against by 6-thioguanine medium. This method provides a suitable alternative to the yeast two-hybrid system and is generally applicable.

scholarly journals Study of Uni-Univalent H+/K+ and Uni-Bivalent H+/Mg2+ Ion Exchange Reactions Using Nuclear Grade Resin Indion-223

2014 ◽  
Vol 33 ◽  
pp. 231-239
Author(s):  
Pravin U. Singare ◽  
Akmal L. Khan Mohammed ◽  
N.N. Dixit
Keyword(s):  
Ion Exchange ◽  
Exchange Resin ◽  
Anion Exchange Resin ◽  
Ionic Species ◽  
Nuclear Grade ◽  
Exchange Reactions ◽  
Process Industries ◽  
Efficient Separation ◽  
Exchange Resins ◽  
Selection Of

In the present paper the uni-univalent and uni-bivalent ion exchange reactions were investigated using nuclear grade anion exchange resin Indion-223 in H+ form. For both H+/K+ uni-univalet ion exchange reactions and H+/Mg2+ uni-bivalet ion exchange reactions, the equilibrium constant K values increases from 0.01710 to 0.02374 and from 0.000177 to 0.000333 respectively as the reaction temperature rises from 35.0 °C to 45.0 °C. The increase in K values with temperature suggest endothermic ion exchange reactions having the enthalpy change values of 22.72 and 51.46 kJ/ mol respectively. The results of such studies will help in selection of suitable ion exchange resins in order to bring about efficient separation of different ionic species present in the waste water effluents released from nuclear as well as chemical process industries.

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