Transfer Learning for Heterocycle Retrosynthesis.

Heterocycles are important scaffolds in medicinal chemistry that can be used to modulate the binding mode as well as the pharmacokinetic properties of drugs. The importance of heterocycles has been exemplified by the publication of numerous data sets containing heterocyclic rings and their properties. However, those data sets lack synthetic routes toward the published heterocycles.

Chloride Selective, Nonprotonophoric Ion Transport with Macrocyclic Halogen Bonding Anionophores.

Synthetic ion transporters hold promise as both chemical probes and potential therapeutics for diseases linked to malfunctioning protein ion transporters. However, their application in biological systems is limited, partly due to the cytotoxicity arising from unselective ion transport. Here, we demonstrate that highly active and selective anionophores can be accessed by combining halogen bonding anion recognition with macrocyclic anion encapsulation.

RaPID discovery of cell-permeable helical peptide inhibitors con-taining cyclic β-amino acids against SARS-CoV-2 main protease.

Structurally constrained cyclic β-amino acids are attractive building blocks for peptide drugs because they induce unique and stable conformations. Introduction of (1,2)-2-aminocyclopentanecarboxylic acid [(1,2)-2-ACPC] into peptides stabilizes helical conformations, so improving proteolytic stability and cell membrane permeability. We report on the ribosomal synthesis of a helical peptide library incorporating (1,2)-2-ACPC at every third position and its application for the discovery of SARS-CoV-2 main protease (M) inhibitors.

Binding assays enable discovery of Tet(X) inhibitors that combat tetracycline destructase resistance.

The Tet(X) flavin-dependent monooxygenases enable tetracycline antibiotic resistance by catalysing inactivating hydroxylation, so preventing inhibition of bacterial ribosomes. Tet(X) resistance is growing rapidly, threatening the efficacy of important last-resort tetracyclines such as tigecycline. Tet(X) inhibitors have potential to protect tetracyclines in combination therapies, but their discovery has been hampered by lack of high-throughput assays.

Dissecting the Effects of Cage Structure in the Catalytic Activation of Imide Chlorenium-Ion Donors.

Imide-based chlorinating reagents are mild and easy to use yet can lack the reactivity of charged chlorenium-ion donors. Here, we present a simple strategy for increasing the reactivity of these neutral chlorinating species by encapsulation inside a cationic coordination cage. Using this approach, we demonstrate that two different-sized PdL cages can catalyze chlorolactonization and chlorocycloetherification reactions of acid and alcohol functionalized α and β-substituted styrene substrates with either 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) or -chlorosuccinimide (NCS) as the chlorenium sources.

Dynamic Kinetic Resolution Allows Control of Remote Stereochemistry in Asymmetric Hydrogen Borrowing Alkylation.

A catalytic asymmetric method for the synthesis of γ-substituted ketones via hydrogen borrowing alkylation of both racemic linear precursors and 1,5-diols is described. The base mediated racemization of an intermediate cyclohexenone to facilitates a dynamic kinetic resolution, affording highly enantioenriched cyclohexanes in excellent yields, which could be further functionalized by removal of the Ph* group. DFT modelling revealed the mode of enantioinduction to be a stepwise process comprising of a hydride transfer and a coordination change to a π-allylic enolate complex with the iridium catalyst.

Stimuli-responsive anion transport utilising caged hydrazone-based anionophores.

Ion transport across biological membranes, facilitated by naturally occurring ion channels and pumps, plays a crucial role in biological processes. Gating is an important aspect of these systems, whereby transport is regulated by a range of external stimuli such as light, ligands and membrane potential. While synthetic ion transport systems, especially those with gating mechanisms, are rare, they have garnered significant attention due to their potential applications in targeted therapeutics as anticancer agents or to treat channelopathies.

Efficacy of the fungus Purpureocillium lilacinum applied via drone onto pasture for controlling the tick Rhipicephalus (Boophilus) microplus (Acari: Ixodidae).

In the southeastern region of Brazil, ticks of the species Rhipicephalus (B.) microplus are constantly present on cattle throughout the year. This is due to climatic conditions that favor the biology of these ticks and resistance to the acaricides in use that has developed.

: Automated Force-Field Parameterization of Covalently Bound Metals for Supramolecular Structures.

Metal ions play a central, functional, and structural role in many molecular structures, from small catalysts to metal-organic frameworks (MOFs) and proteins. Computational studies of these systems typically employ classical or quantum mechanical approaches or a combination of both. Among classical models, only the covalent metal model reproduces both geometries and charge transfer effects but requires time-consuming parameterization, especially for supramolecular systems containing repetitive units.

Modelling ligand exchange in metal complexes with machine learning potentials.

Metal ions are irreplaceable in many areas of chemistry, including (bio)catalysis, self-assembly and charge transfer processes. Yet, modelling their structural and dynamic properties in diverse chemical environments remains challenging for both force fields and methods. Here, we introduce a strategy to train machine learning potentials (MLPs) using MACE, an equivariant message-passing neural network, for metal-ligand complexes in explicit solvents.

Impact of a simple informative leaflet on Brazilian doctors' attitudes towards active surveillance of thyroid microcarcinomas.

Introduction: Active surveillance (AS) is increasingly recognized as an appropriate strategy for selected patients with papillary thyroid microcarcinomas (PTMC). However, some factors, including physician-related ones, hinder its widespread adoption.

Methods: To explore the prevailing barriers and the impact of information on attitudes towards AS implementation, we developed a questionnaire that was completed before and after reading a simple information leaflet by 317 doctors working in different work environments.

Bimolecular Sandwich Aggregates of Porphyrin Nanorings.

Extended π-systems often form supramolecular aggregates, drastically changing their optical and electronic properties. However, aggregation processes can be difficult to characterize or predict. Here, we show that butadiyne-linked 8- and 12-porphyrin nanorings form stable and well-defined bimolecular aggregates with remarkably sharp NMR spectra, despite their dynamic structures and high molecular weights (12.

Modelling chemical processes in explicit solvents with machine learning potentials.

Solvent effects influence all stages of the chemical processes, modulating the stability of intermediates and transition states, as well as altering reaction rates and product ratios. However, accurately modelling these effects remains challenging. Here, we present a general strategy for generating reactive machine learning potentials to model chemical processes in solution.

α-Amino bicycloalkylation through organophotoredox catalysis.

Bridged bicycloalkanes such as bicyclo[1.1.1]pentanes (BCPs) and bicyclo[3.

CageCavityCalc (3): A Computational Tool for Calculating and Visualizing Cavities in Molecular Cages.

Organic(porous) and metal-organic cages are promising biomimetic platforms with diverse applications spanning recognition, sensing, and catalysis. The key to the emergence of these functions is the presence of well-defined inner cavities capable of binding a wide range of guest molecules and modulating their properties. However, despite the myriad cage architectures currently available, the rational design of structurally diverse and functional cages with specific host-guest properties remains challenging.

Origins of High-Activity Cage-Catalyzed Michael Addition.

Cage catalysis continues to create significant interest, yet catalyst function remains poorly understood. Herein, we report mechanistic insights into coordination-cage-catalyzed Michael addition using kinetic and computational methods. The study has been enabled by the detection of identifiable catalyst intermediates, which allow the evolution of different cage species to be monitored and modeled alongside reactants and products.

Beyond Strain Release: Delocalization-Enabled Organic Reactivity.

The release of strain energy is a fundamental driving force for organic reactions. However, absolute strain energy alone is an insufficient predictor of reactivity, evidenced by the similar ring strain but disparate reactivity of cyclopropanes and cyclobutanes. In this work, we demonstrate that electronic delocalization is a key factor that operates alongside strain release to boost, or even dominate, reactivity.

In vitro evaluation of the potential of mites of the family Macrochelidae (Acari: Mesostigmata) as macrobiological agents against the nematode Haemonchus contortus (Strongylida: Trichostrongylidae).

Small ruminants (sheep and goats) constantly suffer from endoparasitoses caused by gastrointestinal nematodes. Among these, the species Haemonchus contortus (Rudolphi, 1803) is considered to be the one of greatest importance within sheep farming. This nematode is difficult to control due to its resistance to most commercial anthelmintics.

Mobile Molecules: Reactivity Profiling Guides Faster Movement on a Cysteine Track.

We previously reported a molecular hopper, which makes sub-nanometer steps by thiol-disulfide interchange along a track with cysteine footholds within a protein nanopore. Here we optimize the hopping rate (ca. 0.

Responsive Anionophores with AND Logic Multi-Stimuli Activation.

Artificial ion transport systems have emerged as an important class of compounds that promise applications in chemotherapeutics as anticancer agents or to treat channelopathies. Stimulus-responsive systems that offer spatiotemporally controlled activity for targeted applications remain rare. Here we utilize dynamic hydrogen bonding interactions of a 4,6-dihydroxy-isophthalamide core to generate a modular platform enabling access to stimuli-responsive ion transporters that can be activated in response to a wide variety of external stimuli, including light, redox, and enzymes, with excellent OFF-ON activation profiles.

Calculation of solar ultraviolet influx in the eye considering the field of view and pupillary dilation due to sunglasses.

The media and even the specialized literature report that the ultraviolet (UV) protection for sunglasses is critical, on the grounds that sunglasses can have a counter effect if the lenses do not provide adequate UV protection. They reason that the primary and natural mechanism is that the pupil of the eye contracts to attenuate radiation and protect the inner eye under sun exposure. Therefore, if dark lenses do not provide appropriate UV protection, there is an increased UV incidence in the inner eye due to pupil dilation, which enhances the adverse effects and impacts the ocular tissues more severely than in situations without UV protection.

Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2' proline of the viral polyprotein.

The SARS-CoV-2 papain-like protease (PL) is an antiviral drug target that catalyzes the hydrolysis of the viral polyproteins pp1a/1ab, so releasing the non-structural proteins (nsps) 1-3 that are essential for the coronavirus lifecycle. The LXGG↓X motif in pp1a/1ab is crucial for recognition and cleavage by PL. We describe molecular dynamics, docking, and quantum mechanics/molecular mechanics (QM/MM) calculations to investigate how oligopeptide substrates derived from the viral polyprotein bind to PL.