bluuebunny/crossref_metadata_2025 huggingface dataset:
InFrag: Using Attribution-based Explainability to Guide Deep Molecular Optimization
Authors: Wüthrich Pierre , Choong Jun Jin , Yuki Shinya
Published: February 2022

The recently proposed Genetic expert guided learning (GEGL) framework has demonstrated impressive performances on several \textit{de novo} molecular design tasks. Despite the displayed state-of-the art results, the proposed system relies on an expert-designed Genetic expert. Although hand-crafted experts allow to navigate the chemical space efficiently, designing such experts requires a significant amount of effort and might contain inherent biases which can potentially slow down convergence or even lead to sub-optimal solutions. In this research, we propose a novel genetic expert named \textit{InFrag} which is free of design rules and can generate new molecules by combining promising molecular fragments. Fragments are obtained by using an additional graph convolutional neural network which computes attributions for each atom for a given molecule. Molecular substructures which contribute positively to the task score are kept and combined to propose novel molecules. We experimentally demonstrate that, within the GEGL framework, our proposed attribution-based genetic expert is either competitive or outperforms the original expert-designed genetic expert on goal-directed optimization tasks. When limiting the number of optimization rounds to one and three rounds, a performance increase of approximately 43% and 20% respectively is observed compared to the baseline genetic expert. Furthermore, we empirically show that combining several experts that share a fixed sampling budget at each optimization round generally improves or maintains the overall performance of the framework.
DockStream: A Docking Wrapper to Enhance De Novo Molecular Design
Authors: Guo Jeff , Janet Jon Paul , Bauer Matthias R. , Nittinger Eva , Giblin Kathryn A. , Papadopoulos Kostas , Voronov Alexey , Patronov Atanas , Engkvist Ola , Margreitter Christian
Published: February 2022

Recently, we have released the de novo design platform REINVENT in version 2.0. This improved and extended iteration supports far more features and scoring function components, which allows bespoke and tailor-made protocols to maximize impact in small molecule drug discovery projects. A major obstacle of generative models is producing active compounds, in which predictive (QSAR) models have been applied to enrich target activity. However, QSAR models are inherently limited by their applicability domains. To overcome these limitations, we introduce a structure-based scoring component for REINVENT. DockStream is a flexible, stand-alone molecular docking wrapper that provides access to a collection of ligand embedders and docking backends. Using the benchmarking and analysis workflow provided in DockStream, execution and subsequent analysis of a variety of docking configurations can be automated. Docking algorithms vary greatly in performance depending on the target and the benchmarking and analysis workflow provides a streamlined solution to identifying productive docking configurations. We show that an informative docking configuration can inform the REINVENT agent to optimize towards improving docking scores using public data. With docking activated, REINVENT is able to retain key interactions in the binding site, discard molecules which do not fit the binding cavity, harness unused (sub-)pockets, and improve overall performance in the scaffold-hopping scenario. The code is freely available at https://github.com/MolecularAI/DockStream.
Substituents of life: The most common substituent patterns present in natural products
Authors: Ertl Peter
Published: February 2022

Comparison of substituents present in natural products with the substituents found in average synthetic molecules revealed considerable differences between these 2 groups. The natural products substituents contain mostly oxygen atoms and very little other heteroatoms, are structurally more complex, often containing double bonds and are rich in stereocenters. Substituents found in synthetic molecules contain nitrogen and sulfur atoms, halogenes and more aromatic and particularly heteroaromatic rings. The characteristics of substituents typical for natural products identified here can be useful in the medicinal chemistry context, for example to guide the synthesis of natural product-like libraries and natural product-inspired fragment collections. The results may be used also to support compound derivatization strategies and the design of pseudo-natural natural products.
Biophysical and in silico characterization of NrtA: A protein-based host for aqueous nitrate and nitrite recognition
Authors: Ji Ke , Baek Kiheon , Peng Weicheng , Alberto Kevin , Torabifard Hedieh , Nielsen Steven , Dodani Sheel
Published: February 2022

Nitrate and nitrite are key components of the global nitrogen cycle. As such, Nature has evolved proteins as biological supramolecular hosts for the recognition, translocation, and transformation of both nitrate and nitrite. To understand the supramolecular principles that govern these anion-protein interactions, here, we employ a hybrid biophysical and in silico approach to characterize the thermodynamic properties and protein dynamics of NrtA from the cyanobacterium Synechocystis sp. PCC 6803 for the recognition of nitrate and nitrite.
Geometry Optimization Speedup Through a Geodesic Approach to Internal Coordinates
Authors: Hermes Eric , Sargsyan Khachik , Najm Habib , Zádor Judit
Published: February 2022

We present a new geodesic-based method for geometry optimization in a basis of redundant internal coordinates. Our method updates the molecular geometry by following the geodesic generated by a displacement vector on the internal coordinate manifold, which dramatically reduces the number of steps required to converge to a minimum. Our method can be implemented in any existing optimization code, requiring only implementation of derivatives of the Wilson B-matrix and the ability to numerically solve an ordinary differential equation.
Engineered Substrates Reveal Species-Specific Inorganic Cues for Coral Larval Settlement
Authors: Levenstein Mark A. , Marhaver Kristen L. , Quinlan Zachary A. , Tholen Haley M. , Tichy Lucas , Yus Joaquín , Lightcap Ian , Wegley Kelly Linda , Juarez Gabriel , Vermeij Mark J. A. , Wagoner Johnson Amy J.
Published: February 2022

The widespread loss of stony reef-building coral populations has been compounded by pervasive recruitment failure, i.e., the low or absent settlement and survival of coral juveniles. To combat global coral reef stressors and rebuild coral communities, restoration practitioners have developed workflows to rear and settle vulnerable coral larvae in the laboratory and subsequently outplant settled juveniles back to natural and artificial reefs. These workflows often make use of the natural biochemical settlement cues present in crustose coralline algae (CCA), which can be presented to swimming larvae as extracts, fragments, or live algal sheets to induce settlement. In this work, we investigated the potential for inorganic chemical cues to complement these known biochemical effects. We designed settlement substrates made from lime mortar (CaCO3) and varied their composition with the use of synthetic and mineral additives, including sands, glasses, and alkaline earth carbonates. In experiments with larvae of two Caribbean coral species, Acropora palmata (elkhorn coral) and Diploria labyrinthiformis (grooved brain coral), we saw additive-specific settlement preferences (>10-fold settlement increase) in the absence of any external biochemical cues. Interestingly, these settlement trends were independent of bulk surface properties such as surface roughness and wettability. Instead, our results suggest that not only can settling coral larvae sense and positively respond to soluble inorganic materials, but that they can also detect localized topographical features more than an order of magnitude smaller than their body width. Our findings open a new area of research in coral reef restoration, in which engineered substrates can be designed with a combination of organic and inorganic additives to increase larval settlement, and perhaps also improve post-settlement growth, mineralization, and defense.
Hydrogen peroxide disproportionation: time-resolved optical measurements of spectra, scattering and imaging combined with correlation analysis and simulations
Authors: Ibrahim Mohamed , Nome Rene
Published: February 2022

We study how time-dependent optical measurements of spectra, scattering, and imaging can be used to add to the understanding of heterogeneous reactions, compared to work performed using tools developed for homogeneous reactions. Using hydrogen peroxide disproportionation by potassium permanganate as a model reaction, we measure the entire spectrum over reaction time, enabling a clear and useful correlation analysis and assignment of chemical species in heterogeneous conditions. We measure time-dependent dynamic light scattering to study oxygen nanobubble product formation kinetics and equilibrium. We perform macroscopic video-rate reaction imaging and information-theoretic analysis to characterize reaction and transport contributions to the observed signal. To illustrate the differences arising from measuring sample subsets vs the entire system, we integrate stochastic and macroscopic numerical simulations of reaction-diffusion to study homogeneous and heterogeneous reaction conditions. We hope the tools presented here may help understanding other chemical reactions in heterogeneous conditions.
Collision-Induced Unfolding of Native-like Protein Ions Within a Trapped Ion Mobility Spectrometry Device
Authors: Borotto Nicholas , Osho Kemi , Richards Talitha , Graham Katherine
Published: February 2022

Native mass spectrometry and collision-induced unfolding (CIU) workflows continue to grow in utilization due to their abil-ity to rapidly characterize protein conformation and stability. To perform these experiments, the instrument must be capa-ble of collisionally activating ions prior to ion mobility spectrometry (IMS) analyses. Trapped ion mobility spectrometry (TIMS) is an ion mobility implementation that continues to grow in utilization due to its inherently high resolution and re-duced instrumental footprint. In currently deployed instruments, however, typical modes of collisional activation do not precede IMS analysis and thus, the instruments are incapable of performing CIU workflows. In this work, we expand on a recently developed method of activating protein ions within the TIMS device and explore its analytical utility toward the unfolding of protein ions. We demonstrate the unfolding of native-like ions of ubiquitin, cytochrome C, β-lactoglobulin, and carbonic anhydrase. These ions undergo extensive unfolding upon collisional activation. Additionally, the improved resolu-tion provided by the TIMS separation uncovers previously obscured unfolding complexity.
Modulating the Frontier Orbitals of an Aluminylene for Facile Dearomatization of Inert Arenes
Authors: Zhang Xin , Liu Liu Leo
Published: February 2022

Lewis bases are well known to stabilize electron-deficient species. We demonstrate herein that the redox property of a monocoordinated aluminylene 1 featuring only four valence electrons for the shell of Al can be boosted by a Lewis base. The coordination of 1 with an N-heterocyclic carbene (NHC) effectively shrinks the HOMO−LUMO gap, thereby enhancing the reactivity of the ensuing acyclic mono-NHC-stabilized aluminylene 2, which is isoelectronic with singlet carbenes. Moreover, such base coordination completely reverses the predominant chemical reactivity (i.e. electrophilicity/nucleophilicity) of aluminylenes. In marked contrast to 1, 2 readily undergoes a [4+1] cycloaddition reaction with naphthalene and biphenylene at room temperature. Remarkably, the enhanced ambiphilic nature of Al in 2 also enables facile cleavage of aromatic C−C bonds of inert arenes in both intra- and intermolecular fashion affording 3 and 5. The formation of 5 represents the first example of the cleavage of aromatic C(3)−C(4) bond in biphenylene by a single atom center.
Lewis acid activation of Weiss’ Reagents ([PhI(Pyr)2]2+) with boranes and isolation of [PhI(4-DMAP)]2+
Authors: Dutton Jason , Clegg Jack , Wilson David , Poynder Tiffany , Bakro Aseel , Sharp-Bucknall Lachlan
Published: February 2022

Abstraction of a pyridine ligand from Weiss’ reagent ([PhI(Pyr)2]2+) using BF3-Et2O was found to activate Weiss’ reagent towards electrophilic aromatic substitution reactions. The activated species can be isolated when 4-DMAP is used as the pyridine ligand and was determined to be a [PhI(4-DMAP)]2+ in solution, and is associated with a triflate counterion in the solid state. The isolated cation was reactive in electrophilic aromatic substitution reactions towards mesitylene, xylene and toluene that Weiss’ reagent itself does not react with. If pyridine is used as the ligand the intermediate that results from abstraction cannot be isolated but is even more active, being observed to react with benzene.
Lighting up Electrochemiluminescent Inactive Dyes by Intramolecular Resonance Energy Transfer
Authors: Zheng Yongjun , Yang Hong , Zhao Lufang , Bai Yuhan , Chen Xinghua , Wu Kaiqing , Liu Songqin , Shen Yanfei , Zhang Yuanjian
Published: February 2022

By virtue of near-zero optical background and photobleaching, electrochemiluminescence (ECL), an optical phenomenon excited by electrochemical reactions, has drawn extensive attention in both fundamental studies and wide applications especially of ultrasensitive bioassay. Developing diverse ECL emitters is crucial to unlock their multiformity and performances, but remains a formidable challenge, due to the rigorous requirements for ECL. Herein, we report a general intramolecular ECL resonance energy transfer (iECL-RET) strategy to light up ECL-inactive dyes in aqueous solutions using an existing high-performance ECL initiators. As a proof-of-concept, a series of luminol donor-dye acceptor based ECL emitters with near unity RET efficiency and coarse/fine tunable emission wavelengths were demonstrated. Different to previous exploitation of new molecule single-handedly to address all the prerequisites of ECL, each unit in the proposed ECL ensemble performed maximally its own functions. The iECL-RET strategy would greatly expand the family members of ECL emitters for more demanding future applications.
Stability of oxidized states of ceria-supported PtOx particles under a wide range of gas-phase conditions
Authors: Quinlivan Domínguez Jon Eunan , Neyman Konstantin , Bruix Albert
Published: February 2022

Nanostructured materials based on non-inert oxides CeO2 and PtyOx play a fundamental role in catalyst design. However, their characterization is often challenging due to their structural complexity and the tendency of the materials to change under reaction conditions. In this work, we combine calculations based on the density functional theory, a machine-learning assisted global optimization method (GOFEE) and ab initio thermodynamics to characterize stable oxidation states of ceria-supported PtyOx clusters in different environments. The collection of global minima for different stoichiometries resulting from the global optimisation effort is used to assess the effect of temperature, oxygen pressure, and support interactions on the phase diagrams, oxidation states, and structural properties of the PtyOx particles. We thus identify favoured structural motifs and O/Pt ratios, revealing that oxidized states of ceria-supported particles are more stable than reduced ones under a wide range of conditions. These results indicate that studies rationalizing activity of ceria-supported Pt clusters must consider such oxidized states, and that previous understanding of such materials obtained only with fully reduced Pt clusters may be incomplete.
Combining Metal-Metal Cooperativity, Metal-Ligand Cooperativity and Chemical Non-Innocence in Diiron Carbonyl Complexes
Authors: Beek Cody Bernard , van Leest Nicolaas P. , Lutz Martin , Klein Gebbink Robertus J. M. , de Bruin Bas , Broere Daniël Laurens Johannes
Published: February 2022

Several metalloenzymes, including [FeFe]-hydrogenase, employ cofactors wherein multiple metal atoms work together with surrounding ligands that mediate heterolytic and concerted proton-electron transfer (CPET) bond activation steps. Herein, we report a new dinucleating PNNP expanded pincer ligand, which can bind two low-valent iron atoms in close proximity to enable metal-metal cooperativity (MMC). In addition, reversible partial dearomatization of the ligand’s naphthyridine core enables both heterolytic metal-ligand cooperativity (MLC) and chemical non-innocence through CPET steps. Thermochemical and computational studies show how a change in ligand binding mode can lower the bond dissociation free energy of ligand C(sp3)–H bonds by ~25 kcal mol-1. H-atom abstraction enabled trapping of an unstable intermediate, which undergoes facile loss of two carbonyl ligands to form an unusual paramagnetic (S = 1/2) complex containing a mixed-valent iron(0)-iron(I) core bound within a partially dearomatized PNNP ligand. Finally, cyclic voltammetry experiments showed that these diiron complexes show catalytic activity for the electrochemical hydrogen evolution reaction. This work presents the first example of a ligand system that enables MMC, heterolytic MLC and chemical non-innocence, thereby providing important insights and opportunities for the development of bimetallic systems that exploit these features to enable new (catalytic) reactivity.
SAXS-WAXS monitoring of the amyloid fibril assembly of a hormone peptide analogue upon pH change.
Authors: GOBEAUX Frédéric , David CARRIERE , WIEN Frank , DATTANI Rajeev
Published: February 2022

Amyloid structures represent one of the most widespread and stable protein folding in nature. This particular folding can be either beneficial or detrimental to its host organism depending on the conditions and places of aggregation. Consequently, the space and time control of their formation mechanisms of amyloid fibril formation is crucial. In the present work, we have investigated the assembly properties of the terlipressin (TLP), a peptide analogue of the vasopressin hormone that is known – like many other peptide hormones – to be stored under the form of reversible amyloid fibrils, which suggests a finely tuned aggregation process. In particular, the assembly kinetics has been monitored by small and wide-angle x-ray scattering (SAXS-WAXS). In combination with circular dichroism, ATR-FTIR and cryoTEM characterization, this analysis reveals that the TLP assembly goes through the formation of on-pathway transitory amorphous aggregates in which the amyloid fibrils nucleate. At the end of the process, the “amyloid phase” (i.e., the fibrils) is in dynamic equilibrium with the liquid phase (peptide monomers). The proportion between the two phases depends on the pH and peptide concentration. Finally, the reversibility of the assembly is assessed.
Tandem C–O and C–H Activation at Palladium Enables Catalytic Direct C–H Alkenylation with Enol Pivalates
Authors: Pipaon Fernandez Nahiane , Gaube Gregory , Woelk Kyla , Burns Mathias , Leitch David
Published: February 2022

The use of oxygen-based electrophiles in cross-coupling remains challenging for substrates with strong C–O bonds, with few examples that can combine C–O activation with an-other strong-bond activation in tandem. We report the first example of a direct, tandem C–O/C–H activation approach to C–C bond formation using palladium catalysis. This reaction combines C–O oxidative addition at enol pivalates with con-certed metallation deprotonation of functionalized heterocycles to achieve base-free direct C–H alkenylation, with pivalic acid as the only byproduct. Mechanistic studies reveal that the Pd(II) C–O oxidative addition product is the major catalyst resting state, indicating that C–H activation is the turnover-limiting step.
A 47-year-old misunderstanding: Indomethacin Polymorph δ revealed to be two plastically bendable crystal forms by 3D electron diffraction
Authors: Lightowler Molly , Li Shuting , Ou Xiao , Zou Xiaodong , Lu Ming , Xu Hongyi
Published: February 2022

Indomethacin is a clinically classical non-steroidal anti-inflammatory drug that has been marketed since 1965. The third polymorph, Form δ, was discovered by both melt and solution crystallization in 1974. δ-indomethacin cannot be cultivated as a large single crystal suitable for X-ray crystallography and, therefore, its crystal structure has not yet been determined. Here, we report the structure elucidation of δ-indomethacin by 3D electron diffraction and reveal the truth that melt-crystallized and solution-crystallized δ-indomethacin are in fact two polymorphs with different crystal structures. Intriguingly, both structures display plastic flexibility based on a slippage mechanism, making indomethacin the first drug to have two plastic polymorphs. This discovery and correction of a 47-year-old misunderstanding signify that 3D electron diffraction has become a powerful tool for polymorphic structural studies.
Multiplexed screening of thousands of natural products for protein-ligand binding in native mass spectrometry
Authors: Nguyen Giang , Bennett Jack , Liu Sherrie , Hancock Sarah , Winter Daniel , Glover Dominic , Donald William
Published: February 2022

The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, novel natural product ligands of human drug targets could be identified without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.
Repurposing 57 well-known drugs for three COVID-19 targets: Mpro, Spike, RdRp
Authors: Nelakuditi Bhavishya , Shrivastava Awantika
Published: February 2022

The pandemic that we are currently living through, caused by SARS COVID-19, changed the way we perceive deadly diseases along with our comprehension of efficacious drugs. In this project, we compare 57 repurposable drugs from different categories like anti-inflammatory, anticancer, anticoagulant, antiviral, anti-parasitic, antidepressant, Parkinson’s disease drugs, and discontinued drugs, to identify the best drugs with strongest binding affinities, that can be considered for treating COVID-19. We identified three target proteins- Main protease (PDB ID: 6LU7), Spike Glycoprotein with human receptor ACE2 (PDB ID: 6M0J), and RNA-dependent RNA polymerase (RdRp) in complex with Remdesivir (PDB ID: 7BV2) which are responsible for transcription, entrance into host’s cell and viral replication respectively. We used AutoDock Vina for docking, and based our results on the binding affinity and hydrogen bond interactions. We shortlisted 15 drugs- Vilazodone, Lopinavir, Ritonavir, Darunavir, Selinexor, Etoposide, Nintedanib, Methylprednisolone, Hydrocortisone, Tolcapone, Apixaban, Rivaroxaban, Dabigatran, Betrixaban, and Amprenavir- that showcased comparable or higher affinity than Remdesivir with all of our three target proteins, and recommend these for further studies.
Understanding the Crucial Significance of the Temperature and Potential Window on the Stability of Carbon Supported Pt-alloy Nanoparticles as Oxygen Reduction Reaction Electrocatalysts
Authors: Đukić Tina , Jean Moriau Leonard , Pavko Luka , Kostelec Mitja , Prokop Martin , Ruiz-Zepeda Francisco , Šala Martin , Dražić Goran , Gatalo Matija , Hodnik Nejc
Published: February 2022

The present research provides a comprehensive study of carbon-supported intermetallic Pt-alloy electrocatalysts and assesses their stability against metal dissolution in relation to the operating temperature and the potential window using two advanced electrochemical methodologies: (i) the in-house designed high-temperature disk electrode (HT-DE) methodology as well as (ii) a modification of the electrochemical flow cell coupled to an inductively coupled plasma mass spectrometer (EFC-ICP-MS), allowing for highly sensitive time- and potential-resolved measurements of metal dissolution. The findings contradict the generally accepted hypothesis that in contrast to the rate of carbon corrosion, which follows the Arrhenius law and increases exponentially with temperature, the kinetics of Pt and subsequently the less noble metal dissolution are supposed to be for the most part unaffected by temperature. On the contrary, clear evidence is presented that in addition to the importance of the voltage/potential window, the temperature is one of the most critical parameters governing the stability of Pt and thus, in the case of Pt-alloy electrocatalysts also the ability of the nanoparticles (NPs) to retain the less noble metal. Lastly, but also very importantly, results indicate that the rate of Pt redeposition significantly increases with temperature, which has been the main reason why mechanistic interpretation of the temperature-dependent kinetics related to the stability of Pt remained highly speculative until now.
On the electrooxidation of glucose on gold: towards an electrochemical glucaric acid production as value-added chemical
Authors: Schlegel Nicolas , Wiberg Gustav , Arenz Matthias
Published: February 2022

The electrocatalytic oxidation of glucose to value-added chemicals, such as glucaric acid, has gathered increased interest in recent years. Glucose oxidation is a promising process which has the potential to contribute to establishing renewable resources as alternatives to fossil carbon sources. Herein, we present rotating disk electrode (RDE) studies on polycrystalline gold surfaces and subsequent Koutecký-Levich analysis as a benchmark to expand the understanding of reaction kinetics and competition between glucose, reaction intermediates and OH- at the catalyst surface. Combining electrochemical studies and Raman spectroscopy, it is shown that increasing glucose concentrations lead to a delayed oxidation of the gold catalyst surface, presumably by increased consumption rates of Au-hydroxide species.
Programmable cell-free transcriptional switches for antibodies detection
Authors: Patiño Diaz Aitor , Bracaglia Sara , Ranallo Simona , Patiño Tania , Porchetta Alessandro , Ricci Francesco
Published: February 2022

We report here the development of a cell-free in-vitro transcription system for the detection of specific target antibodies. The approach is based on the use of programmable antigen-conjugated DNA-based conformational switches that, upon binding to a target antibody, can trigger the cell-free transcription of a light-up fluorescence-activating RNA aptamer. The system couples the unique programmability and responsiveness of DNA-based systems with the specificity and sensitivity offered by in-vitro genetic circuitries and commercially available transcription kits. We demonstrate that cell-free transcriptional switches can efficiently measure antibody levels directly in blood serum. Thanks to the programmable nature of the sensing platform the method can be adapted to different antibodies: we demonstrate here the sensitive, rapid and cost-effective detection of three different antibodies and the possible use of this approach for the simultaneous detection of two antibodies in the same solution.
1H NMR Elucidation of Observed Stable Sugar-NaCl-water Complexes in Aqueous Solution
Authors: Zhu Gan , Li Hui , Li Yiqun , Gu Liuqun
Published: February 2022

The solvation of sugars in aqueous media matters in understanding of biological system and in carbohydrate transformations. Generally, 2 – 4 water units were proposed to interact with each hydroxyl group in monosaccharides via different types of hydrogen bondings at room temperature in previous study. Presence of NaCl was known to perturb hydrogen bondings of sugar hydrates, however direct evidence to elucidate mechanism at atom level is very rare even though “NaCl Effect” was well known in biomass chemical transformations. Here we reported 1H NMR elucidation evidences of mono/disaccharides hydrates in different concentration of NaCl aqueous solutions. We here conclude two new findings: 1) under ideal usage of NaCl, different mono/disaccharides hydrates were likely converted into a stable sugar-NaCl-water form; 2) pKa value of different hydroxyls in mono/disaccharides has intangible influence on hydrate form change induced by NaCl. A proposed ideal NaCl usage based on maximum of 1H NMR shift is consistent with optimized condition in reported literature.
1H NMR Elucidation of Observed Stable Sugar-NaCl-water Complexes in Aqueous Solution
Authors: Zhu Gan , Li Hui , Li Yiqun , Gu Liuqun
Published: February 2022

The solvation of sugars in aqueous media matters in the understanding of biological systems and carbohydrate transformations. Generally, 2 – 4 water units were proposed to interact with each hydroxyl group in monosaccharides via different types of hydrogen bondings at room temperature in previous studies. Presence of NaCl was known to perturb hydrogen bondings of sugar hydrates. However, direct evidence to elucidate mechanism at atom level is very rare even though “NaCl Effect” was well known in biomass chemical transformations. Here we report 1H NMR elucidation evidences of mono/disaccharides hydrates in different concentration of NaCl aqueous solutions. We here conclude two new findings: 1) under ideal usage of NaCl, different mono/disaccharides hydrates are likely to be converted into a stable sugar-NaCl-water form; 2) pKa value of different hydroxyls in mono/disaccharides has intangible influence on hydrate form change induced by NaCl. An ideal NaCl usage based on maximum of 1H NMR shift was proposed.
Studies of Catalyst-Controlled Regioselective Acetalization and Its Application to Single-Pot Synthesis of Differentially Protected Saccharides.
Authors: Wang Sibin , Zhelavskyi Oleksii , Lee Jeonghyo , Arguelles Alonso J. , Khomutnyk Yaroslav , Mensah Enoch A. , Guo Hao , Hourani Rami , Zimmerman Paul M. , Nagorny Pavel
Published: February 2022

This article describes the studies on regioselective acetal protection of monosaccharide-based diols using chiral phos-phoric acids (CPAs) and their immobilized polymeric variants, (R)-Ad-TRIP-PS and (S)-SPINOL-PS as the catalysts. These catalyst-controlled regioselective acetalizations were found to proceed with high regioselectivities (up to >25:1 rr) on various D-glucose, D-galactose, D-mannose and L-fucose derived 1,2-diols, and could be carried in a re-giodivergent fashion depending on the choice of the chiral catalyst. The polymeric catalysts were conveniently recy-cled and reused multiple times for gram scale functionalizations with catalytic loading as low as 0.1 mol%, and their performance was often found to be superior to the performance of their monomeric variants. These regioselective CPA-catalyzed acetalizations were successfully combined with common hydroxyl group functionalizations as single-pot telescoped procedures to produce 34 regioisomerically pure differentially protected mono- and disaccharide de-rivatives. To further demonstrate the utility of the polymeric catalysts, the same batch of (R)-Ad-TRIP-PS catalyst was recycled and reused to accomplish single-pot gram-scale syntheses of 6 differentially protected D-glucose derivatives. The subsequent exploration of the reaction mechanism using NMR studies of deuterated and nondeuterated sub-strates revealed that low-temperature acetalizations happen via syn-addition mechanism, and that the reaction regi-oselectivity exhibits strong dependence on the temperature. The computational studies indicate complex tempera-ture-dependent interplay of two reaction mechanisms, one involving an anomeric phosphate intermediate and an-other via concerted asynchronous formation of acetal that results in syn-addition products. The computational models also explain the steric factors responsible for the observed C2-selectivities and are consistent with experimentally observed selectivity trends.
Active Meta-Learning for Predicting and Selecting Perovskite Crystallization Experiments
Authors: Shekar Venkateswaran , Nicholas Gareth , Najeeb Mansoor Ani , Zeile Margaret , Yu Vincent , Wang Xiaorong , Slack Dylan , Li Zhi , Nega Philip , Chan Emory , Norquist Alexander , Schrier Joshua , Friedler Sorelle
Published: February 2022

Autonomous experimentation systems use algorithms and data from prior experiments to select and perform new experiments in order to meet a specified objective. In most experimental chemistry situations there is a limited set of prior historical data available, and acquiring new data may be expensive and time consuming, which places constraints on machine learning methods. Active learning methods prioritize new experiment selection by using machine learning model uncertainty and predicted outcomes. Meta-learning methods attempt to construct models that can learn quickly with a limited set of data for a new task. In this paper, we applied the model-agnostic meta-learning (MAML) model and Probabilistic LATent model for Incorporating Priors and Uncertainty in few-Shot learning (PLATIPUS) approach, which extends MAML to active learning, to the problem of halide perovskite growth by inverse temperature crystallization. Using a dataset of 1870 reactions conducted using 19 different organoammoniumn lead iodide systems, we determined the optimal strategies for incorporating historical data into active and meta-learning models. We then evaluated the best three algorithms (PLATIPUS, and active-learning k-Nearest Neighbor and Decision Tree algorithms) with four new chemical systems in experimental laboratory tests. With a fixed budget of 20 experiments, PLATIPUS makes superior predictions of reaction outcome compared to other active-learning algorithms and a random baseline.
An Integrative Resource for Network-Based Investigation of COVID-19 Combinatorial Drug Repositioning and Mechanism of Action
Authors: Azad A K M , Fatima Shadma , Capraro Alexander , Waters Shafagh A. , Vafaee Fatemeh
Published: February 2022

An effective monotherapy to target the complex and multifactorial pathology of SARS-CoV-2 infection poses a challenge to drug repositioning, which can be improved by combination therapy. We developed an online network pharmacology-based drug repositioning platform, COVID-CDR (http://vafaeelab.com/COVID19repositioning.html), that enables a visual and quantitative investigation of the interplay between the drug primary targets and the SARS-CoV-2–host interactome in the human protein-protein interaction network. COVID-CDR prioritizes drug combinations with the potential to act synergistically through different, yet potentially complementary pathways. It provides the options for understanding multi-evidence drug-pair similarity scores along with several other relevant information on individual drugs or drug pairs. Overall, COVID-CDR is the first-of-its-kind online platform that provides a systematic approach for pre-clinical in silico investigation of combination therapies for treating COVID-19 at the fingertips of the clinicians and researchers.
Untethering sparteine: 1,3-diamine ligand for asymmetric synthesis in water
Authors: Zeng Fanyun , Chen Chen , Liu Liu , Li Yifan , Li Bo , Lin Guotao , Huang Shihao , Zhang Mingyu , Yan Yuting , Zhang Yuan , Dang Yanfeng , Huang Jianhui
Published: February 2022

Chiral ligands are the toolbox for asymmetric synthesis to access 3D molecular world. Enabling efficient asymmetric reaction in water is a big challenge. As moisture/air stable and strong binding moieties, amines, compared to imine and phosphine ligands, are ideal candidates to accommodate asymmetric transformations in water. Known amine ligands like Proline analogues and Cinchona alkaloids showed excellent asymmetric induction. Sparteine, an alkaloid studied originated in 1968, had never been considered as a privileged catalyst due to its structure defection which led to poor reaction compatibility and unsatisfactory stereoselectivity. Here, we report the design of a chiral diamine catalyst untethering one of the sparteine rings. The diamine catalyst was easily accessed in two steps on 100 gram-scale. This chiral ligand was proved to be efficient for addition reactions in water providing products with excellent yields and enantiomeric ratios. This pluripotent catalyst has also shown good reactivity/enantioselectivity under organocatalysis, Cu and Pd-catalysed conditions. We anticipate that the ligand would allow further development of other catalysts for important yet challenging green stereoselective transformations.
Microbial fuel cell power overshoot studied with microfluidics: from quantification to elimination
Authors: Amirdehi Mehran Abbaszadeh , Gong Lingling , Khodaparastasgarabad Nastaran , Logan Bruce E. , Greener Jesse
Published: February 2022

Power overshoot can hinder determination of maximum power densities in microbial fuel cells (MFCs). In this work, a microfluidic approach was used to study overshoot in an MFC containing a pure culture of electroactive biofilms (EAB) containing Geobacter sulfurreducens. After 1-month operation under constant flow of an ideal nutrient medium, the MFC health began to degrade, marked by voltage loss and the appearance of anomalies in the power density curves. One such anomaly was a chronic power overshoot, accompanying a loss of both measured power and current density on the high-current side of the power density curve. The degree of power overshoot was quantified while certain flow-based interventions were applied, notably the shear erosion of the EAB outer layer. Next, two approaches to acclimation were demonstrated to treat the remaining overshoot. The standard approach, which acclimates the MFC to high currents before a standard polarization test, eliminated the remaining overshoot and returned maximum power densities to initial levels, but maximum current density remained lower than the initial level. A microfluidic-assisted “long-hold polarization test” enabled efficient in situ acclimation of each external resistor during the measurement. Despite the health-compromised MFC, this method provided long-term stability during the polarization test, resulting in power and current density measurements that exceeded those made on the healthy MFC using the standard polarization test. We conclude that slower electron transfer kinetics in unhealthy MFCs can provoke overshoot by prolonging the time to reach steady state during the polarization test, but a properly designed measurement overcomes this problem.
Superphanes: Facile and Efficient Preparation, Functionalization and Unique Properties
Authors: Li Aimin , Liu Yuanchu , Zhou Wei , Jiang Yunqi , He Qing
Published: February 2022

Superphanes, compounds in which the two benzene rings clamped parallel on top of each other by six bridges, have garnered considerable interest due to their aesthetically pleasing structures and unique chemical physical properties. However, until now progress in the research of superphane chemistry and beyond has been seriously hampered by their poor availability. Herein, we report the facile and scalable synthesis of a collection of superphanes with structural diversity and their unique photophysical properties, as well as their unusual host–guest behavior. Initially, a set of dodecaimino–containing super-phanes 7a–7e are obtained via dynamic self–assembly of a hexakis–amine and a series of readily derived aromatic dialde-hyde in one pot. The resulting superphanes are found capable of being reduced with NaBH4 to their corresponding second-ary–amine versions 3a–3e. Subsequently, superphane 3c bearing 12 amine–NHs was further subject to post–functionalization with various functional groups, e.g., ethyl, allyl, propargyl and but–2–yn–1–yl. Unprecedentedly, the sec-ondary amine–based superphanes 3a–3e were observed to exhibit genuine fluorescence both in solution and in the solid state while the imine–based superphanes 7a–7e were found to highly emissive only in solid state with fluorescent quantum yields of 3.5 ~ 17.1. Finally, fully protonated 3a was exemplified to encapsulate a 2Cl–·H2O cluster both in the solid state and in solution. With the easy and versatile synthesis, modification, as well as unique photophysical and host–guest properties, we believe that this study will break the bottleneck in superphane chemistry and open the door to a novel class of supramo-lecular hosts and advanced functional materials on the basis of superphanes.
Catalytic Carbochlorocarbonylation of Unsaturated Hydrocarbons via C–COCl Bond Cleavage
Authors: Denton Elliott , Lee Yong Ho , Roediger Sven , Boehm Philip , Fellert Maximillian , Morandi Bill
Published: February 2022

Here we report a palladium-catalysed intermolecular difunctionalisation of unsaturated C–C bonds with acid chlorides. Specifically, the C–COCl bond of an acid chloride is cleaved and added, with complete atom economy, across either strained alkenes or tethered alkynes to generate new acid chlorides. The transformation does not require exogenous carbon monoxide, operates under mild conditions, shows a good functional group tolerance, and occurs with excellent stereoselectivity. The intermolecular reaction tolerates both aryl- and alkenyl-substituted acid chlorides and is successful when carboxylic acids are transformed to the acid chloride in situ. The reaction also shows an example of temperature-dependent stereodivergence which, together with plausible mechanistic pathways, is investigated by DFT calculations. Moreover, we show that benzofurans can be formed in an intramolecular variant of the reaction. Finally, derivation of the products from the intermolecular reaction provides a highly stereoselective approach for the synthesis of tetrasubstituted cyclopentanes.
Development and Application of ReaxFF Methodology for Understanding the Chemical Dynamics of Metal Carbonates in Aqueous Solutions
Authors: Dasgupta Nabankur , Chen Chen , van Duin Adri
Published: February 2022

A new ReaxFF reactive force field has been developed for metal carbonate systems including Na+, Ca2+, and Mg2+ cations and the CO32- anion. This force field is fully transferable with previous ReaxFF water and water/electrolyte descriptions. The Me-O-C three-body valence angle parameters and Me-C non-reactive parameters of the force field have been optimized against quantum mechanical calculations including equations of states, heats of formation, heats of reaction, angle distortions and vibrational frequencies. The new metal carbonate force field has been validated using molecular dynamics simulations to study solvation and reactivity of metal and carbonate ions in water at 300 K and 700 K. The coordination radius and self-diffusion coefficient show good consistency with existing experiments and simulations results. The angular distribution analysis explains the structural preference of carbonate ions to form carbonates and bicarbonates, where Na+ predominantly forms carbonates due to lesser angular strain, while Ca2+ and Mg2+ prefer to form bicarbonates monodentate in nature. Residence time distribution analyses on different systems reveal the role of ions in accelerating and decelerating dynamics of water and carbonate ions under different thermodynamic conditions. The formation and dissolution of bicarbonates and carbonates in the solution were explored on the basis of protonation capability in different systems. The nucleation phenomenon of metal carbonates at ambient and supercritical conditions is explained from the perspective of clusters formation over time: Ca2+ ions can form prenucleation clusters at ambient temperature but shows a saturation with temperature, whereas Na+ and Mg2+ ions show rapid increase in cluster size and amount upon increasing time and temperature.
On the role of long-range electrostatics in machine-learned interatomic potentials for complex battery materials
Authors: Staacke Carsten G. , Heenen Hendrik H. , Scheurer Christoph , Csányi Gábor , Reuter Karsten , Margraf Johannes T.
Published: February 2022

Modeling complex energy materials such as solid-state electrolytes (SSEs) realistically at the atomistic level strains the capabilities of state-of-the-art theoretical approaches. On one hand, the system sizes and simulation time scales required are prohibitive for first-principles methods like density functional theory (DFT). On the other hand, parameterizations for empirical potentials are often not available and these potentials may ultimately lack the desired predictive accuracy. Fortunately, modern machine learning (ML) potentials are increasingly able to bridge this gap, promising first-principles accuracy at a much reduced computational cost. However, the local nature of these ML potentials typically means that long-range contributions arising, e.g., from electrostatic interactions are neglected. Clearly, such interactions can be large in polar materials like electrolytes, however. Herein, we investigate the effect that the locality assumption of ML potentials has on lithium mobility and defect formation energies in the SSE Li$_7$P$_3$S$_{11}$. We find that neglecting long-range electrostatics is unproblematic for the description of lithium transport in the isotropic bulk. In contrast (field-dependent) defect formation energies are only adequately captured by a hybrid potential combining ML and a physical model of electrostatic interactions. Broader implications for ML based modelling of energy materials are discussed.
SynthI: a new open-source tool for synthon-based library design
Authors: Varnek Alexandre , Zabolotna Yuliana , Volochnyuk Dmitriy , Ryabukhin Sergey , Gavrylenko Kostiantyn , Horvath Dragos , Klimchuk Olga , Oksiuta Olexandr , Marcou Gilles
Published: February 2022

Here we present a new open-source toolkit for library design, called Synthons Interpreter or SynthI that allows merging those chemical space of the retrosynthetically generated fragments and the pool of available reagents into a single synthons space. Here synthons are defined as the actual fragments with valid valences and special labels, defining the position and nature of reactive centers. They can be issued from either the “break-up” of reference compounds according to retrosynthetic rules, or real reagents/BBs, after leaving groups transformation. Such an approach not only enables the design of synthetically accessible libraries and analogs generation but also facilitates BB analysis in the medicinal chemistry context. SynthI code is available in https://github.com/Laboratoire-de-Chemoinformatique/SynthI