Covalent fragment libraries in drug discovery-Design, synthesis, and screening methods.

As the development of drugs with a covalent mode of action is becoming increasingly popular, well-validated covalent fragment-based drug discovery (FBDD) methods have been comparatively slow to keep up with the demand. In this chapter the principles of covalent fragment reactivity, library design, synthesis, and screening methods are explored in depth, focussing on literature examples with direct applications to practical covalent fragment library design and screening. Further, questions about the future of the field are explored and potential useful advances are proposed.

Impact of an educational intervention for advanced cancer patients referred for early phase clinical trials.

A 2017 service evaluation identified a lack of information and knowledge among patients who were referred on to early phase oncology clinical trials (Hood, 2020). An educational booklet was developed to improve patients' knowledge and experience. To build upon this work, a patient co-designed website was developed. This study examined the impact, if any, of a patient co-designed educational intervention within the clinical pathway for patients who are referred for an early phase oncology clinical trial at an experimental cancer medicine centre (ECMC). AIMS: 1. To understand the experiences of patients who have been referred to an ECMC for an early phase clinical trial pre- and post-intervention. 2. To investigate if the intervention reduced anxiety levels in newly referred patients. METHOD: A convergent mixed-methods design was used in this study, to collect quantitative and qualitative data in parallel. OUTCOMES: This study examined the experiences of advanced cancer patients who attended their initial research outpatient appointment to discuss the possibility of taking part in an early phase clinical trial and the impact of an educational resource.

Effectiveness of a neonatal COVID-19 response project: A mixed-methods evaluation using the Donabedian model.

Objective: This article outlines notable findings of a service evaluation of a COVID-19 response project, the Nurture Project (July 2020-March 2021). Method: The Donabedian structure-process-outcome model was used. Mixed-methods online surveys and organisational data were analysed using reflexive thematic analysis and statistical analysis methods. Results: Most staff and service users were satisfied with the project, reporting positive benefits to mental health, child development, and wellbeing. However, project outcome measures (Generalised Anxiety Disorder Scale GAD-7 and the Patient Health Questionnaire PHQ-9) were statistically non-significant. Conclusion: Although the project was considered successful, recommendations for future service evaluation methods, outcome measurement, and future research are provided.

Synthesis of Sulfoximine Propargyl Carbamates under Improved Conditions for Rhodium Catalyzed Carbamate Transfer to Sulfoxides.

Sulfoximines provide aza-analogues of sulfones, with potentially improved properties for medicinal chemistry. The sulfoximine nitrogen also provides an additional vector for the inclusion of other functionality. Here, we report improved conditions for rhodium catalyzed synthesis of sulfoximine (and sulfilimine) carbamates, especially for previously low-yielding carbamates containing π-functionality. Notably we report the preparation of propargyl sulfoximine carbamates to provide an alkyne as a potential click handle. Using Rh2(esp)2 as catalyst and a DOE optimization approach provided considerably increased yields.

Co-ordinated control of the Aurora B abscission checkpoint by PKCε complex assembly, midbody recruitment and retention.

A requirement for PKCε in exiting from the Aurora B dependent abscission checkpoint is associated with events at the midbody, however, the recruitment, retention and action of PKCε in this compartment are poorly understood. Here, the prerequisite for 14-3-3 complex assembly in this pathway is directly linked to the phosphorylation of Aurora B S227 at the midbody. However, while essential for PKCε control of Aurora B, 14-3-3 association is shown to be unnecessary for the activity-dependent enrichment of PKCε at the midbody. This localisation is demonstrated to be an autonomous property of the inactive PKCε D532N mutant, consistent with activity-dependent dissociation. The C1A and C1B domains are necessary for this localisation, while the C2 domain and inter-C1 domain (IC1D) are necessary for retention at the midbody. Furthermore, it is shown that while the IC1D mutant retains 14-3-3 complex proficiency, it does not support Aurora B phosphorylation, nor rescues division failure observed with knockdown of endogenous PKCε. It is concluded that the concerted action of multiple independent events facilitates PKCε phosphorylation of Aurora B at the midbody to control exit from the abscission checkpoint.

Synthesis and Configurational Assignment of Vinyl Sulfoximines and Sulfonimidamides.

Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologies for constructing vinyl sulfoximine and vinyl sulfonimidamide architectures that allows access to new areas of electrophilic chemical space. We demonstrate how late-stage functionalization can be applied to these motifs to incorporate alkyne tags, generating fully functionalized probes for future chemical biology applications. Finally, we establish a workflow for determining the absolute configuration of enantioenriched vinyl sulfoximines and sulfonimidamides by comparing experimentally and computationally determined electronic circular dichroism spectra, enabling access to configurationally assigned enantiomeric pairs by separation.

Multiparameter Kinetic Analysis for Covalent Fragment Optimization by Using Quantitative Irreversible Tethering (qIT).

Chemical probes that covalently modify cysteine residues in a protein-specific manner are valuable tools for biological investigations. Covalent fragments are increasingly implemented as probe starting points, but the complex relationship between fragment structure and binding kinetics makes covalent fragment optimization uniquely challenging. We describe a new technique in covalent probe discovery that enables data-driven optimization of covalent fragment potency and selectivity. This platform extends beyond the existing repertoire of methods for identifying covalent fragment hits by facilitating rapid multiparameter kinetic analysis of covalent structure-activity relationships through the simultaneous determination of Ki , kinact and intrinsic reactivity. By applying this approach to develop novel probes against electrophile-sensitive kinases, we showcase the utility of the platform in hit identification and highlight how multiparameter kinetic analysis enabled a successful fragment-merging strategy.

An augmented reality approach for ADL support in Alzheimer's disease: a crossover trial.

BACKGROUND: Dementia of the Alzheimer's type can impair the performance of activities of daily living and therefore severely impact independent living. Assistive technologies can support such patients when carrying out daily tasks. METHODS: In this crossover study, we used an augmented reality approach using a Microsoft HoloLens to support patients in a tea making task. During task execution, subjects received three-dimensional dynamic holograms of the sub-steps necessary to complete the task. Ten patients suffering from Alzheimer's disease were tested and post-hoc semi-structured interviews were conducted to assess usability. RESULTS: The patients committed errors when executing the task with and without holographic assistance. No differences in success rates or error frequencies were observed (psuccess = .250, perrors = .887). Patients revealed prolonged trial durations (Glass' Δ = 1.475) when wearing the augmented reality headset. A model of multiple linear regression (R2adjusted = .958) revealed an influence of the errors in the control condition and a moderation by the errors in the experimental condition. Patients with more severe problems in the natural performance of the task showed lower increases in trial durations when wearing the HoloLens. CONCLUSIONS: We assume that the application was a secondary task requesting its own resources and impairing performance on its own. The regression suggests however that the given assistance was compensating these additional costs in patients with stronger needs of support. Interview data on usability revealed an overall positive feedback towards the application although the hardware was considered uncomfortable and too large. We conclude that the approach proved feasible and the acceptability was overall high, although advances in hardware and the patient-interface are necessary to assist patients suffering from Alzheimer's disease in daily activities. TRIAL REGISTRATION: DRKS, DRKS00014870. Registered 11 June 2018 - Retrospectively registered, TrialID = DRKS00014870 .

High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery.

Cysteine-reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-selective allosteric (type IV) kinase inhibitor whose novel mode-of-action could be exploited therapeutically.

Explaining Anomalies in Enamine Catalysis: "Downstream Species" as a New Paradigm for Stereocontrol.

Enantioselective organocatalysis by diarylprolinol ethers is remarkably selective and efficient for a wide range of transformations involving a number of different activation modes, including HOMO activation via enamines. A simple steric model based on facial discrimination in the attack of an enamine on an electrophile has been invoked to rationalize high enantioselectivity. In a number of reactions, however, experimental observations have persistently left us with mechanistic puzzles that fail to fit neatly into this simple picture. Further studies involving both kinetic profiling of reaction networks and NMR spectroscopic characterization of the structures of intermediate species helped us to address these puzzles. This work led to the proposal of a new paradigm for stereocontrol in asymmetric aminocatalysis, demonstrating that the ultimate stereochemical outcome may not, in fact, be determined solely in the stereogenic bond-forming step between enamine and electrophile. The identification of stable species occurring downstream from the addition of an electrophile to an enamine, and the discovery of kinetic features that are diagnostic of the presence of such species, allows development of a new mechanistic framework that reveals a hierarchical selection. Both kinetic and thermodynamic processes associated with downstream intermediates can exert an influence on the ultimate enantioselectivity. Interestingly, the role of these species may be either to enhance or to erode selectivity established at the enamine-electrophile step. The reversibility of steps preceding and subsequent to the stereogenic bond-forming step is an important factor, as are reaction parameters that may stabilize or destabilize intermediates, including the nature of the electrophile counterion and the solvent. These concepts hold implications for the future design and optimization of asymmetric catalytic processes, because such design does not necessarily feature the same parameters at the second hierarchical level as it does at the first. Examples presented to highlight these issues include the conjugate addition of aldehydes to nitroalkenes and the α-chlorination and α-selenylation of aldehdyes using diarylprolinol ether catalysts commonly assumed to follow a steric model for enantioselectivity. While the new paradigm for stereocontrol involving downstream intermediates is developed here for enamine catalysis, the same concepts may hold for other organocatalytic modes of activation.

Synthesis, characterisation and reactivity of copper(I) amide complexes and studies on their role in the modified Ullmann amination reaction.

A series of copper(I) alkylamide complexes have been synthesised; copper(I) dicyclohexylamide (1), copper(I) 2,2,6,6-tetramethylpiperidide (2), copper(I) pyrrolidide (3), copper(I) piperidide (4), and copper(I) benzylamide (5). Their solid-state structures and structures in [D6 ]benzene solution are characterised, with the aggregation state in solution determined by a combination of DOSY NMR spectroscopy and DFT calculations. Complexes 1, 2 and 4 are shown to exist as tetramers in the solid state by X-ray crystallography. In [D6 ]benzene solution, complexes 1, 2 and 5 were found by using (1) H DOSY NMR to exist in rapid equilibrium between aggregates with average aggregation numbers of 2.5, 2.4 and 3.3, respectively, at 0.05 M concentration. Conversely, distinct trimeric, tetrameric and pentameric forms of 3 and 4 were distinguishable by one-dimensional (1) H and (1) H DOSY NMR spectroscopy. Complexes 3-5 are found to react stoichiometrically with iodobenzene, in the presence or absence of 1,10-phenanthroline as an ancillary ligand, to give arylamine products indicative of their role as potential intermediates in the modified Ullmann reaction. The role of phenanthroline has also been explored both in the stoichiometric reaction and in the catalytic Ullmann protocol.

[2,3]-Sigmatropic rearrangement of allylic selenimides: strategy for the synthesis of peptides, peptidomimetics, and N-aryl vinyl glycines.

The scope of the NCS-mediated amination/[2,3]-sigmatropic rearrangement of enantioenriched allylic selenides has been expanded to provide access to three new product classes. The use of N-protected amino acid amides provides a novel strategy for accessing peptide chains containing unnatural vinyl glycine amino acid residues. Also reported is the use of amino acid esters, allowing the diastereoselective synthesis of N,N-dicarboxymethylamines, a motif found in a number of pharmaceuticals. Furthermore, use of a range of N-aromatic and N-heteroaromatic amines allows the formation of enantioenriched N-arylamino acids, a motif found in a number of synthetically and biologically interesting compounds.

Sensorimotor synchronization with audio-visual stimuli: limited multisensory integration.

Understanding how we synchronize our actions with stimuli from different sensory modalities plays a central role in helping to establish how we interact with our multisensory environment. Recent research has shown better performance with multisensory over unisensory stimuli; however, the type of stimuli used has mainly been auditory and tactile. The aim of this article was to expand our understanding of sensorimotor synchronization with multisensory audio-visual stimuli and compare these findings to their individual unisensory counterparts. This research also aims to assess the role of spatio-temporal structure for each sensory modality. The visual and/or auditory stimuli had either temporal or spatio-temporal information available and were presented to the participants in unimodal and bimodal conditions. Globally, the performance was significantly better for the bimodal compared to the unimodal conditions; however, this benefit was limited to only one of the bimodal conditions. In terms of the unimodal conditions, the level of synchronization with visual stimuli was better than auditory, and while there was an observed benefit with the spatio-temporal compared to temporal visual stimulus, this was not replicated with the auditory stimulus.

Rationalization of an unusual solvent-induced inversion of enantiomeric excess in organocatalytic selenylation of aldehydes.

An unusual solvent-induced inversion of the sense of enantioselectivity observed in the α-selenylation of aldehydes catalyzed by a diphenylprolinol silyl ether catalyst is correlated to the presence of intermediates formed subsequent to the highly selective C-Se bond-forming step in the catalytic cycle. This work provides support for a mechanistic concept for enamine catalysis and includes a general role for "downstream intermediates" in selectivity outcomes in organocatalysis.

Application of occupational justice concepts to children who are born preterm or admitted to neonatal intensive care and their parents: a scoping review protocol.

OBJECTIVE: This review aims to identify and map the usage, application, and context of occupational justice concepts and related terms by occupational therapists and occupational scientists in relation to parents and children when children are born preterm or admitted to a neonatal intensive care unit. INTRODUCTION: Occupational justice concepts and related terms can inform occupational therapy practice at the individual level or as a wider social approach. However, the extent to which these concepts have been applied to parents and children, when children are born preterm or admitted to neonatal intensive care, is unknown. INCLUSION CRITERIA: Studies must include 1 or more occupational justice concepts or associated terms in relation to the named population groups. Sources must be related to occupational therapy or occupational science. METHODS: The review will follow the JBI methodology for scoping reviews and will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and the PRISMA-S extension for reporting literature searches in systematic reviews. Several electronic databases and sources of gray literature will be searched, limited by publication year (2000 till the present day). The review will only include human studies and studies with a title or abstract in English. Book chapters will be excluded. Reference lists of included studies will be searched against pre-determined criteria. Evidence sources will be independently screened by a minimum of 2 authors, and evidence will be mapped on a pre-determined template. DETAILS OF THE REVIEW AVAILABLE AT: Open Science Framework https://osf.io/fgd7n.

Infection prevention and control measures for preterm infants discharged into the community: a scoping review protocol.

BACKGROUND: Infection prevention and control (IPC) is an evidence-based and practical approach to prevention of harm by infection (Infection prevention and control https://www.who.int/health-topics/infection-prevention-and-control#tab=tab_1 ). IPC recommendations targeted at community-acquired infection aim to prevent illness and subsequent hospital readmission. Cohesive guidance for parents of preterm infants has not been clearly established. The review objectives are to identify and map the global characteristics of IPC measures/recommendations for parents of preterm infants discharged home to the community. METHODS: The scoping review will be conducted using the JBI methodological approach for scoping reviews and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review extension (PRISMA ScR) and the PRISMA extension for reporting literature searches in systematic reviews. Electronic databases will be searched and limited by publication year (2013-present day). Grey literature, reference lists and expert-provided sources will be searched against predetermined criteria. A minimum of two authors will independently screen evidence sources and chart evidence on a predetermined charting form. Sources including IPC measures, or recommendations for parents of preterm infants during discharge planning or in the community/home, will be permitted within inclusion criteria. Limits include human studies only and evidence from 2013-present day. Recommendations aimed at professional implementation will be excluded. A descriptive summary of findings will be presented, with diagrammatic and tabular representation. DISCUSSION: Collated evidence will guide future research which will subsequently aim to develop policy and enhance clinical approaches. SYSTEMATIC REVIEW REGISTRATION: This review has been registered on the Open Science Framework (OSF) 4th May 2021, available at https://osf.io/9yhzk .

Implementation of 'One Health' approach in Kerala state, India - A systematic review.

With humans, animals and the environment being as interconnected as they are, the science describing their interactions needs to cut across disciplinary boundaries. Systems research at the interface between the three goes by several names, such as 'Eco-Health' and 'Planetary Health', each with a varied focus, but the concept of 'One Health' (OH) has stood out as the most popular one. COVID-19 has reiterated the importance of OH in response to health challenges. This review aimed to assess the OH approach integration and implementation level in Kerala state, India, in the context of emerging zoonotic diseases. A systematic literature review was conducted by searching for relevant articles with specific keywords across six electronic databases. This involved screening the initial hits for titles and abstracts, then systematic sorting to identify the ones that met the criteria, followed by more thorough scrutiny to finally shortlist the six studies to be included in the review. We found that OH in Kerala has made good progress, as evident from a few recent examples, but has a long way to go with significant challenges. In line with the study's aim, identifying and analysing what is already done, what is missing and what needs to be done can have wider implications for future OH implementation. Relevant threats and opportunities were identified, with lessons for Kerala and India and broader applications.

Uncovering the Most Kinetically Influential Reaction Pathway Driving the Generation of HCN from Oxyma/DIC Adduct: A Theoretical Study.

The combination of ethyl (hydroxyimino)cyanoacetate (Oxyma) and diisopropylcarbodiimide (DIC) has demonstrated superior performance in amino acid activation for peptide synthesis. However, it was recently reported that Oxyma and DIC could react to generate undesired hydrogen cyanide (HCN) at 20 °C, raising safety concerns for the practical use of this activation strategy. To help minimize the risks, there is a need for a comprehensive investigation of the mechanism and kinetics of the generation of HCN. Here we show the results of the first systematic computational study of the underpinning mechanism, including comparisons with experimental data. Two pathways for the decomposition of the Oxyma/DIC adduct are derived to account for the generation of HCN and its accompanying cyclic product. These two mechanisms differ in the electrophilic carbon atom attacked by the nucleophilic sp2-nitrogen in the cyclization step and in the cyclic product generated. On the basis of computed "observed" activation energies, ΔG obs ⧧, the mechanism that proceeds via the attack of the sp2-nitrogen at the oxime carbon is identified as the most kinetically favorable one, a conclusion that is supported by closer agreement between predicted and experimental 13C NMR data. These results can provide a theoretical basis to develop a design strategy for suppressing HCN generation when using Oxyma/DIC for amino acid activation.

Curtin-Hammett paradigm for stereocontrol in organocatalysis by diarylprolinol ether catalysts.

Detailed mechanistic study of two reactions catalyzed by diarylprolinol ether catalysts, the conjugate addition of aldehydes to nitro-olefins and the α-chlorination of aldehydes, leads to the proposal that the stereochemical outcome in these cases is not determined by the transition state of the step in which the stereogenic center is formed from enamine attack on the electrophile but instead is correlated with the relative stability and reactivity of diastereomeric intermediates downstream in the catalytic cycle. This combination of kinetic and thermodynamic factors illustrates a remarkable Curtin-Hammett scenario that can result in either an enhancement or an erosion of the selectivity that would be predicted by the transition state for enamine attack on the electrophile. Evidence is offered to suggest that this concept may represent a general phenomenon for pyrrolidine-based catalysts lacking an acidic directing proton. Implications for catalyst and reaction design are discussed.

Thermodynamic control of asymmetric amplification in amino acid catalysis.

Ever since Pasteur noticed that tartrate crystals exist in two non-superimposable forms that are mirror images of one another--as are left and right hands--the phenomenon of chirality has intrigued scientists. On the molecular level, chirality often has a profound impact on recognition and interaction events and is thus important to biochemistry and pharmacology. In chemical synthesis, much effort has been directed towards developing asymmetric synthesis strategies that yield product molecules with a significant excess of either the left-handed or right-handed enantiomer. This is usually achieved by making use of chiral auxiliaries or catalysts that influence the course of a reaction, with the enantiomeric excess (ee) of the product linearly related to the ee of the auxiliary or catalyst used. In recent years, however, an increasing number of asymmetric reactions have been documented where this relationship is nonlinear, an effect that can lead to asymmetric amplification. Theoretical models have long suggested that autocatalytic processes can result in kinetically controlled asymmetric amplification, a prediction that has now been verified experimentally and rationalized mechanistically for an autocatalytic alkylation reaction. Here we show an alternative mechanism that gives rise to asymmetric amplification based on the equilibrium solid-liquid phase behaviour of amino acids in solution. This amplification mechanism is robust and can operate in aqueous systems, making it an appealing proposition for explaining one of the most tantalizing examples of asymmetric amplification-the development of high enantiomeric excess in biomolecules from a presumably racemic prebiotic world.