Harnessing methylation and AdoMet-utilising enzymes for selective modification in cascade reactions

2021 ◽  
Author(s):  
Freideriki Michailidou ◽  
Andrea Rentmeister
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Cascade Reactions ◽  
Fine Tuning ◽  
Wide Range

Enzyme-mediated methylation is a very important reaction in nature, yielding a wide range of modified natural products, diversifying small molecules and fine-tuning the activity of biomacromolecules. The field has attracted...

Understanding Conformational Entropy in Small Molecules

2020 ◽  
Author(s):  
Lucian Chan ◽  
Garrett Morris ◽  
Geoffrey Hutchison
Keyword(s):  
Small Molecules ◽  
Degrees Of Freedom ◽  
Absolute Error ◽  
Low Energy ◽  
Standard Entropy ◽  
Free Energies ◽  
Conformational Entropy ◽  
Wide Range ◽  
High Degree ◽  
Empirical Corrections

The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers grows exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations, and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically-motivated statistical model can outperform common machine learning and deep learning methods, with a mean absolute error ≈4.8 J/mol•K, or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often as- sumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom, and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations, and advance our understanding of small molecule conformational entropy.

Investigating the influence of aromatic moieties on the formulation of hydrophobic natural products and drugs in poly(2-oxazoline) based amphiphiles

2018 ◽  
Author(s):  
Robert Luxenhofer ◽  
Michael M Lübtow ◽  
Lukas Hahn ◽  
Thomas Lorson ◽  
Rainer Schobert
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Water Solubility ◽  
Drug Loading ◽  
High Drug ◽  
Long Term Stability ◽  
Aromatic Content ◽  
Important Interaction ◽  
Amorphous Structures ◽  
High Drug Loading

Many natural compounds with interesting biomedical properties share one physicochemical property, namely a low water solubility. Polymer micelles are, among others, a popular means to solubilize hydrophobic compounds. The specific molecular interactions between the polymers and the hydrophobic drugs are diverse and recently it has been discussed that macromolecular engineering can be used to optimize drug loaded micelles. Specifically, π-π stacking between small molecules and polymers has been discussed as an important interaction that can be employed to increase drug loading and formulation stability. Here, we test this hypothesis using four different polymer amphiphiles with varying aromatic content and various natural products that also contain different relative amounts of aromatic moieties. While in the case of paclitaxel, having the lowest relative content of aromatic moieties, the drug loading decreases with increasing relative aromatic amount in the polymer, the drug loading of curcumin, having a much higher relative aromatic content, is increased. Interestingly, the loading using schizandrin A, a dibenzo[a,c]cyclooctadiene lignan with intermediate relative aromatic content is not influenced significantly by the aromatic content of the polymers employed. The very high drug loading, long term stability, the ability to form stable highly loaded binary coformulations in different drug combinations, small sized formulations and amorphous structures in all cases, corroborate earlier reports that poly(2-oxazoline) based micelles exhibit an extraordinarily high drug loading and are promising candidates for further biomedical applications. The presented results underline that the interaction between the polymers and the incorporated small molecules are complex and must be investigated in every specific case.<br>

scholarly journals Modern Synthetic Methods for the Stereoselective Construction of 1,3-Dienes

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 249
Author(s):  
Raquel G. Soengas ◽  
Humberto Rodríguez-Solla
Keyword(s):  
Organic Chemistry ◽  
Natural Products ◽  
Functional Group ◽  
Biological Activities ◽  
Synthetic Methods ◽  
Bond Forming ◽  
Drug Candidates ◽  
The Past ◽  
Wide Range

The 1,3-butadiene motif is widely found in many natural products and drug candidates with relevant biological activities. Moreover, dienes are important targets for synthetic chemists, due to their ability to give access to a wide range of functional group transformations, including a broad range of C-C bond-forming processes. Therefore, the stereoselective preparation of dienes have attracted much attention over the past decades, and the search for new synthetic protocols continues unabated. The aim of this review is to give an overview of the diverse methodologies that have emerged in the last decade, with a focus on the synthetic processes that meet the requirements of efficiency and sustainability of modern organic chemistry.

scholarly journals Suppressing meta-holographic artifacts by laser coherence tuning

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yaniv Eliezer ◽  
Geyang Qu ◽  
Wenhong Yang ◽  
Yujie Wang ◽  
Hasan Yılmaz ◽  
...  
Keyword(s):  
Spatial Coherence ◽  
Fine Tuning ◽  
Total Power ◽  
Image Sharpness ◽  
Continuous Tuning ◽  
Fine Spatial Resolution ◽  
Compact Size ◽  
Wide Range ◽  
Fabrication Defects ◽  
Holographic Displays

AbstractA metasurface hologram combines fine spatial resolution and large viewing angles with a planar form factor and compact size. However, it suffers coherent artifacts originating from electromagnetic cross-talk between closely packed meta-atoms and fabrication defects of nanoscale features. Here, we introduce an efficient method to suppress all artifacts by fine-tuning the spatial coherence of illumination. Our method is implemented with a degenerate cavity laser, which allows a precise and continuous tuning of the spatial coherence over a wide range, with little variation in the emission spectrum and total power. We find the optimal degree of spatial coherence to suppress the coherent artifacts of a meta-hologram while maintaining the image sharpness. This work paves the way to compact and dynamical holographic displays free of coherent defects.

scholarly journals Mini-review: antibody therapeutics targeting G protein-coupled receptors and ion channels

2020 ◽  
Vol 3 (4) ◽  
pp. 257-264
Author(s):  
Catherine J Hutchings
Keyword(s):  
Ion Channels ◽  
Research And Development ◽  
Small Molecules ◽  
G Protein ◽  
Clinical Studies ◽  
G Protein Coupled Receptors ◽  
Protein Targets ◽  
Antibody Therapeutics ◽  
Wide Range ◽  
G Protein Coupled

Abstract Antibodies are now well established as therapeutics with many additional advantages over small molecules and peptides relative to their selectivity, bioavailability, half-life and effector function. Major classes of membrane-associated protein targets include G protein-coupled receptors (GPCRs) and ion channels that are linked to a wide range of disease indications across all therapeutic areas. This mini-review summarizes the antibody target landscape for both GPCRs and ion channels as well as current progress in the respective research and development pipelines with some example case studies highlighted from clinical studies, including those being evaluated for the treatment of symptoms in COVID-19 infection.

scholarly journals Fine-tuning of a generative neural network for designing multi-target compounds

2021 ◽  
Author(s):  
Thomas Blaschke ◽  
Jürgen Bajorath
Keyword(s):  
Neural Network ◽  
Small Molecules ◽  
De Novo ◽  
Pharmaceutical Research ◽  
Generative Models ◽  
Fine Tuning ◽  
Data Sets ◽  
Single Target ◽  
Fine Tune ◽  
Target Activity

AbstractExploring the origin of multi-target activity of small molecules and designing new multi-target compounds are highly topical issues in pharmaceutical research. We have investigated the ability of a generative neural network to create multi-target compounds. Data sets of experimentally confirmed multi-target, single-target, and consistently inactive compounds were extracted from public screening data considering positive and negative assay results. These data sets were used to fine-tune the REINVENT generative model via transfer learning to systematically recognize multi-target compounds, distinguish them from single-target or inactive compounds, and construct new multi-target compounds. During fine-tuning, the model showed a clear tendency to increasingly generate multi-target compounds and structural analogs. Our findings indicate that generative models can be adopted for de novo multi-target compound design.

Alkene Difunctionalization Directed by Free Amines: Diamine Synthesis via Nickel-Catalyzed 1,2-Carboamination

2021 ◽  
Author(s):  
Taeho Kang ◽  
José Manuel González ◽  
Zi-Qi Li ◽  
Klement Foo ◽  
Peter Cheng ◽  
...  
Keyword(s):  
Nickel Catalyst ◽  
Room Temperature ◽  
Kinetic Studies ◽  
Fine Tuning ◽  
Secondary Amines ◽  
Protecting Group ◽  
Wide Range ◽  
Leaving Group ◽  
Primary And Secondary Amines ◽  
Reaction Proceeds

A versatile method to access differentially substituted 1,3- and 1,4-diamines via a nickel-catalyzed three-component 1,2-carboamination of alkenyl amines with aryl/alkenylboronic ester nucleophiles and N–O electrophiles is reported. The reaction proceeds efficiently with free primary and secondary amines without needing a directing auxiliary or protecting group, and is enabled by fine-tuning the leaving group on the N–O reagent. The transformation is highly regioselective and compatible with a wide range of coupling partners and alkenyl amine substrates, all performed at room temperature. A series of kinetic studies support a mechanism in which alkene coordination to the nickel catalyst is turnover-limiting.

Fitting Frequency-Lowering Signal Processing Applying the American Academy of Audiology Pediatric Amplification Guideline: Updates and Protocols

2016 ◽  
Vol 27 (03) ◽  
pp. 219-236 ◽  
Author(s):  
Susan Scollie ◽  
Danielle Glista ◽  
Julie Seto ◽  
Andrea Dunn ◽  
Brittany Schuett ◽  
...  
Keyword(s):  
Signal Processing ◽  
Frequency Response ◽  
Hearing Aids ◽  
Hearing Aid ◽  
Fine Tuning ◽  
Sensation Level ◽  
Response Level ◽  
Strong Basis ◽  
Wide Range ◽  
Signal Processors

Background: Although guidelines for fitting hearing aids for children are well developed and have strong basis in evidence, specific protocols for fitting and verifying technologies can supplement such guidelines. One such technology is frequency-lowering signal processing. Children require access to a broad bandwidth of speech to detect and use all phonemes including female /s/. When access through conventional amplification is not possible, the use of frequency-lowering signal processing may be considered as a means to overcome limitations. Fitting and verification protocols are needed to better define candidacy determination and options for assessing and fine tuning frequency-lowering signal processing for individuals. Purpose: This work aims to (1) describe a set of calibrated phonemes that can be used to characterize the variation in different brands of frequency-lowering processors in hearing aids and the verification with these signals and (2) determine whether verification with these signal are predictive of perceptual changes associated with changes in the strength of frequency-lowering signal processing. Finally, we aimed to develop a fitting protocol for use in pediatric clinical practice. Study Sample: Study 1 used a sample of six hearing aids spanning four types of frequency lowering algorithms for an electroacoustic evaluation. Study 2 included 21 adults who had hearing loss (mean age 66 yr). Data Collection and Analysis: Simulated fricatives were designed to mimic the level and frequency shape of female fricatives extracted from two sources of speech. These signals were used to verify the frequency-lowering effects of four distinct types of frequency-lowering signal processors available in commercial hearing aids, and verification measures were compared to extracted fricatives made in a reference system. In a second study, the simulated fricatives were used within a probe microphone measurement system to verify a wide range of frequency compression settings in a commercial hearing aid, and 27 adult listeners were tested at each setting. The relation between the hearing aid verification measures and the listener’s ability to detect and discriminate between fricatives was examined. Results: Verification measures made with the simulated fricatives agreed to within 4 dB, on average, and tended to mimic the frequency response shape of fricatives presented in a running speech context. Some processors showed a greater aided response level for fricatives in running speech than fricatives presented in isolation. Results with listeners indicated that verified settings that provided a positive sensation level of /s/ and that maximized the frequency difference between /s/ and /∫/ tended to have the best performance. Conclusions: Frequency-lowering signal processors have measureable effects on the high-frequency fricative content of speech, particularly female /s/. It is possible to measure these effects either with a simple strategy that presents an isolated simulated fricative and measures the aided frequency response or with a more complex system that extracts fricatives from running speech. For some processors, a more accurate result may be achieved with a running speech system. In listeners, the aided frequency location and sensation level of fricatives may be helpful in predicting whether a specific hearing aid fitting, with or without frequency-lowering, will support access to the fricatives of speech.

scholarly journals Synthesis of sp3-rich scaffolds for molecular libraries through complexity-generating cascade reactions

2016 ◽  
Vol 14 (21) ◽  
pp. 4943-4946 ◽  
Author(s):  
T. Flagstad ◽  
G. Min ◽  
K. Bonnet ◽  
R. Morgentin ◽  
D. Roche ◽  
...  
Keyword(s):  
Small Molecules ◽  
Building Blocks ◽  
Cascade Reactions ◽  
Efficient Strategy ◽  
Molecular Libraries

An efficient strategy for the synthesis of complex small molecules from simple building blocks is presented.

scholarly journals TSAL: Two steps Adversarial learning based domain adaptation

2021 ◽  
Vol 34 (1) ◽  
Author(s):  
Haidi Hasan Badr ◽  
Nayer Mahmoud Wanas ◽  
Magda Fayek
Keyword(s):  
Network Architecture ◽  
Domain Adaptation ◽  
Data Availability ◽  
Fine Tuning ◽  
Target Domain ◽  
Adversarial Learning ◽  
Prior Art ◽  
Real World Problem ◽  
Wide Range ◽  
Benchmark Datasets

Since labeled data availability differs greatly across domains, Domain Adaptation focuses on learning in new and unfamiliar domains by reducing distribution divergence. Recent research suggests that the adversarial learning approach could be a promising way to achieve the domain adaptation objective. Adversarial learning is a strategy for learning domain-transferable features in robust deep networks. This paper introduces the TSAL paradigm, a two-step adversarial learning framework. It addresses the real-world problem of text classification, where source domain(s) has labeled data but target domain (s) has only unlabeled data. TSAL utilizes joint adversarial learning with class information and domain alignment deep network architecture to learn both domain-invariant and domain-specific features extractors. It consists of two training steps that are similar to the paradigm, in which pre-trained model weights are used as initialization for training with new data. TSAL’s two training phases, however, are based on the same data, not different data, as is the case with fine-tuning. Furthermore, TSAL only uses the learned domain-invariant feature extractor from the first training as an initialization for its peer in subsequent training. By doubling the training, TSAL can emphasize the leverage of the small unlabeled target domain and learn effectively what to share between various domains. A detailed analysis of many benchmark datasets reveals that our model consistently outperforms the prior art across a wide range of dataset distributions.

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