Rational Design Research Articles

A Review on Indole-triazole Molecular Hybrids as a Leading Edge in Drug Discovery: Current Landscape and Future Perspectives.

Molecular hybridization is a rational design strategy used to create new ligands or pro-totypes by identifying and combining specific pharmacophoric subunits from the molecular struc-tures of two or more known bioactive derivatives. Molecular hybridization is a valuable technique in drug discovery, enabling the modulation of unwanted side effects and the creation of potential dual-acting drugs that combine the effects of multiple therapeutic agents. Indole-triazole conju-gates have emerged as promising candidates for new drug development. The indole and triazole moieties can be linked through various synthetic strategies, such as click chemistry or other cou-pling reactions, to generate a library of diverse compounds for biological screening. The achieva-ble structural diversity with indole-triazole conjugates offers avenues to optimize their pharmaco-kinetic and pharmacodynamic attributes, amplifying their therapeutic efficacy. Researchers have extensively tailored both indole and triazole frameworks with diverse modifications to compre-hend their impact on the drug's pharmacokinetic and pharmacodynamic characteristics. The cur-rent review article endeavours to explore and discuss various research strategies to design indole-triazole hybrids and elucidate their significance in a variety of pathological conditions. The in-sights provided herein are anticipated to be beneficial for the researchers and will likely encour-age further exploration in this field.

Systematic metabolic engineering of Zymomonas mobilis for β-farnesene production

Zymomonas mobilis is an ethanologenic bacterium that can produce hopanoids using farnesyl pyrophosphate (FPP), which can be used as the precursor by β-farnesene synthase for β-farnesene production. To explore the possibility and bottlenecks of developing Z. mobilis for β-farnesene production, five heterologous β-farnesene synthases were selected and screened, and AaBFS from Artemisia annua had the highest β-farnesene titer. Recombinant strains with AaBFS driven by the strong constitutive promoter Pgap (Pgap–AaBFS) doubled its β-farnesene production to 25.73 ± 0.31 mg/L compared to the recombinant strain with AaBFS driven by Ptet (Ptet–AaBFS), which can be further improved by overexpressing the Pgap–AaBFS construct using the strategies of multiple plasmids (41.00 ± 0.40 mg/L) or genomic multi-locus integration (48.33 ± 3.40 mg/L). The effect of cofactor NADPH balancing on β-farnesene production was also investigated, which can be improved only in zwf-overexpressing strains but not in ppnK-overexpressing strains, indicating that cofactor balancing is important and sophisticated. Furthermore, the β-farnesene titer was improved to 73.30 ± 0.71 mg/L by overexpressing dxs, ispG, and ispH. Finally, the β-farnesene production was increased to 159.70 ± 7.21 mg/L by fermentation optimization, including the C/N ratio, flask working volume, and medium/dodecane ratio, which was nearly 13-fold improved from the parental strain. This work thus not only generated a recombinant β-farnesene production Z. mobilis strain but also unraveled the bottlenecks to engineer Z. mobilis for farnesene production, which will help guide the future rational design and construction of cell factories for terpenoid production in non-model industrial microorganisms.

Bridged Pt-OH-Mn Mediator in N-coordinated Mn Single Atoms and Pt Nanoparticles for Electrochemical Biomolecule Oxidation and Discrimination.

The rational design of efficient catalysts for uric acid (UA) electrooxidation, as well as the establishment of structure-activity relationships, remains a critical bottleneck in the field of electrochemical sensing. To address these challenges, herein, a hybrid catalyst that integrates carbon-supported Pt nanoparticles and nitrogen-coordinated Mn single atoms (PtNPs/MnNC) is developed. The metal-metal interaction during annealing affords the construction of metallic-bonded Pt-Mn pairs between PtNPs and Mn single atoms, facilitating the electron transfer from PtNPs to the support and thereby optimizing the electronic structure of catalysts. More importantly, experiments and theoretical calculations provide visual proof for the 'incipient hydrous oxide adatom mediator' mechanism for UA oxidation. The Pt-Mn pairs first adsorb OH* to construct the bridged Pt-OH-Mn mediators to serve as a highly active intermediate for N-H bond dissociation and proton transfer. Benefiting from the unique electronic and geometric structure of the catalytic center and reactive intermediates, PtNPs/MnNC exhibits superior electrooxidation performance. The electrochemical sensor based on PtNPs/MnNC enables sensitive detection and discrimination of UA and dopamine in serum samples. This work offers new insights into the construction of novel electrocatalysis for sensitive sensing platforms.

Valence can control the nonexponential viscoelastic relaxation of multivalent reversible gels.

Gels made of telechelic polymers connected by reversible cross-linkers are a versatile design platform for biocompatible viscoelastic materials. Their linear response to a step strain displays a fast, near-exponential relaxation when using low-valence cross-linkers, while larger supramolecular cross-linkers bring about much slower dynamics involving a wide distribution of timescales whose physical origin is still debated. Here, we propose a model where the relaxation of polymer gels in the dilute regime originates from elementary events in which the bonds connecting two neighboring cross-linkers all disconnect. Larger cross-linkers allow for a greater average number of bonds connecting them but also generate more heterogeneity. We characterize the resulting distribution of relaxation timescales analytically and accurately reproduce stress relaxation measurements on metal-coordinated hydrogels with a variety of cross-linker sizes including ions, metal-organic cages, and nanoparticles. Our approach is simple enough to be extended to any cross-linker size and could thus be harnessed for the rational design of complex viscoelastic materials.

Diamond-lattice photonic crystals assembled from DNA origami.

Colloidal self-assembly allows rational design of structures on the micrometer and submicrometer scale. One architecture that can generate complete three-dimensional photonic bandgaps is the diamond cubic lattice, which has remained difficult to realize at length scales comparable with the wavelength of visible or ultraviolet light. In this work, we demonstrate three-dimensional photonic crystals self-assembled from DNA origami that act as precisely programmable patchy colloids. Our DNA-based nanoscale tetrapods crystallize into a rod-connected diamond cubic lattice with a periodicity of 170 nanometers. This structure serves as a scaffold for atomic-layer deposition of high-refractive index materials such as titanium dioxide, yielding a tunable photonic bandgap in the near-ultraviolet.

Structural mechanisms for binding and activation of a contact-quenched fluorophore by RhoBAST.

The fluorescent light-up aptamer RhoBAST, which binds and activates the fluorophore-quencher conjugate tetramethylrhodamine-dinitroaniline with high affinity, super high brightness, remarkable photostability, and fast exchange kinetics, exhibits excellent performance in super-resolution RNA imaging. Here we determine the co-crystal structure of RhoBAST in complex with tetramethylrhodamine-dinitroaniline to elucidate the molecular basis for ligand binding and fluorescence activation. The structure exhibits an asymmetric "A"-like architecture for RhoBAST with a semi-open binding pocket harboring the xanthene of tetramethylrhodamine at the tip, while the dinitroaniline quencher stacks over the phenyl of tetramethylrhodamine instead of being fully released. Molecular dynamics simulations show highly heterogeneous conformational ensembles with the contact-but-unstacked fluorophore-quencher conformation for both free and bound tetramethylrhodamine-dinitroaniline being predominant. The simulations also show that, upon RNA binding, the fraction of xanthene-dinitroaniline stacked conformation significantly decreases in free tetramethylrhodamine-dinitroaniline. This highlights the importance of releasing dinitroaniline from xanthene tetramethylrhodamine to unquench the RhoBAST-tetramethylrhodamine-dinitroaniline complex. Using SAXS and ITC, we characterized the magnesium dependency of the folding and binding mode of RhoBAST in solution and indicated its strong structural robustness. The structures and binding modes of relevant fluorescent light-up aptamers are compared, providing mechanistic insights for rational design and optimization of this important fluorescent light-up aptamer-ligand system.

Rational Design of an Optimal Al-substituted Layered Oxide Cathode for Na-ion Batteries

Layered oxide cathodes, a promising avenue for Na-ion batteries, hold the highest potential for commercialization. Herein, we delve into the structural and electrochemical properties of Al-substituted layered oxides in our quest to pinpoint the optimal cathode composition in the Na3/4(Mn-Al-Ni)O2 pseudo-ternary system. The cathode materials investigated were synthesized in three distinct phase configurations, which include two monophasic configurations with P3 and P2-type structures and a third biphasic cathode with equal proportions of P3 and P2 phases. The fractions of the P3 and P2 type phases in the cathode materials were manipulated by adjusting the calcination temperature. The varying concentration of Mn3+ and Mn4+, confirmed by X-ray photoelectron spectroscopy, was found to impact the cyclic stability of these materials significantly. During electrochemical testing, the P3 cathodes showed impressive rate performance and exhibited an excellent specific capacity of 195 mAh g−1 at 0.1C. Regarding cyclic performance, the biphasic cathodes consistently outperformed their monophasic counterparts, with P3/P2-Na0.75Mn0.50Ni0.25Al0.25O2 exhibiting 82% capacity retention after 300 cycles. Analysis of operando Synchrotron XRD data revealed an absence of P3 to O3 type phase transition in the cathodes even at low voltages where large structural variations to the unit cell structure were observed. The absence of P3 to O3 transformations and the superior electrochemical performance of Na0.75Mn0.50Ni0.25Al0.25O2 underlines the importance of Al substitution and P3/P2 biphasic structure in enhancing the electrochemical performance of layered oxides.

DCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders

DCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders

Bridged Pt–OH–Mn Mediator in N‐coordinated Mn Single Atoms and Pt Nanoparticles for Electrochemical Biomolecule Oxidation and Discrimination

The rational design of efficient catalysts for uric acid (UA) electrooxidation, as well as the establishment of structure‐activity relationships, remains a critical bottleneck in the field of electrochemical sensing. To address these challenges, herein, a hybrid catalyst that integrates carbon‐supported Pt nanoparticles and nitrogen‐coordinated Mn single atoms (PtNPs/MnNC) is developed. The metal‐metal interaction during annealing affords the construction of metallic‐bonded Pt−Mn pairs between PtNPs and Mn single atoms, facilitating the electron transfer from PtNPs to the support and thereby optimizing the electronic structure of catalysts. More importantly, experiments and theoretical calculations provide visual proof for the ‘incipient hydrous oxide adatom mediator’ mechanism for UA oxidation. The Pt−Mn pairs first adsorb OH* to construct the bridged Pt–OH–Mn mediators to serve as a highly active intermediate for N–H bond dissociation and proton transfer. Benefiting from the unique electronic and geometric structure of the catalytic center and reactive intermediates, PtNPs/MnNC exhibits superior electrooxidation performance. The electrochemical sensor based on PtNPs/MnNC enables sensitive detection and discrimination of UA and dopamine in serum samples. This work offers new insights into the construction of novel electrocatalysis for sensitive sensing platforms.

Rational Design of Coumarin-Based Hybridized Local and Charge-Transfer Blue Emitters for Solution-Processed Organic Light-Emitting Diodes.

Hybridized local and charge-transfer (HLCT) with the utilization of both singlet and triplet excitons through the "hot excitons" channel have great application potential in highly efficient blue organic light-emitting diodes (OLEDs). The proportion of charge-transfer (CT) and locally excited (LE) components in the relevant singlet and triplet states makes a big difference for the high-lying reverse intersystem crossing process. Herein, three novel donor (D)-acceptor (A) type HLCT materials, 7-([1,1'-biphenyl]-4-yl(9,9-dimethyl-9H-fluoren-2-yl)amino)-3-phenyl-1H-isochromen-1-one (pPh-7P), 7-([1,1'-biphenyl]-4-yl(9,9-dimethyl-9H-fluoren-2-yl)amino)-3-methyl-1H-isochromen-1-one (pPh-7M), and 6-([1,1'-biphenyl]-4-yl(9,9-dimethyl-9H-fluoren-2-yl)amino)-3-methyl-1H-isochromen-1-one (pPh-6M), were rationally designed and synthesized with diphenylamine derivative as donor and oxygen heterocyclic coumarin moiety as acceptors. The proportions of CT and LE components were fine controlled by changing the connection site of diphenylamine derivative at C6/C7-position and the substituent at C3-position of coumarin moiety. The HLCT characteristics of pPh-7P, pPh-7M, and pPh-6M were systematically demonstrated through photophysical properties and density functional theory calculations. The solution-processed doped OLEDs based on pPh-6M exhibited deep-blue electroluminescence with the maximum emission wavelength of 446 nm, maximum luminance of 8755 cd m-2, maximum current efficiency of 5.83 cd A-1, and maximum external quantum efficiency of 6.54%. The results reveal that pPh-6M with dominant 1LE and 3CT components has better OLED performance.

Cobalt-Catalyzed Domino Transformations via Enantioselective C-H Activation/Nucleophilic [3 + 2] Annulation toward Chiral Bridged Bicycles.

Selective synthesis of chiral bridged (hetero)bicyclic scaffolds via asymmetric C-H activation constitutes substantial challenges due to the multiple reactivities of strained bicyclic structures. Herein, we develop the domino transformations through an unprecedented cobalt-catalyzed enantioselective C-H activation/nucleophilic [3 + 2] annulation with symmetrical bicyclic alkenes. The methods offer straightforward access to a wide range of chiral molecules bearing [2.2.1]-bridged bicyclic cores with four and five consecutive stereocenters in a single step. Two elaborate salicyloxazoline (Salox) ligands were synthesized based on the rational design and mechanistic understanding. The well-defined chiral pockets generated from asymmetric coordination around the trivalent cobalt catalyst direct the orientation of bicyclic alkenes, leading to excellent enantioselectivity.

Piezoelectric Polarization and Sulfur Vacancy Enhanced Photocatalytic Hydrogen Evolution Performance of Bi2S3/ZnSn(OH)6 Piezo-photocatalyst.

The combination of piezoelectric catalysis and photocatalysis could effectively enhance the carrier separation efficiency and further improve the hydrogen production activity. However, piezoelectric polarization always suffers from a low polarization strength, which severely restricts its actual applications. In this study, we successfully synthesized a novel sulfur vacancy-rich Bi2S3/ZnSn (OH)6 (BS-12/ZSH) piezo-photocatalyst for hydrogen evolution through water splitting. Notably, the piezo-photocatalytic hydrogen generation rate of the 8% BS-12/ZSH catalyst (336.21 μmol/g/h) was superior to that of pristine ZSH (29.71 μmol/g/h) and BS-12 (21.66 μmol/g/h). In addition, the hydrogen generation for 8% BS-12/ZSH (336.21 μmol/g/h) under ultrasonic coupling illumination was significantly higher than that under single illumination (52.09 μmol/g/h) and ultrasound (121.90 μmol/g/h), owing to the cooperative interaction of the sulfur vacancy and piezoelectric field. Various characterization analyses confirmed that (1) the introduction of sulfur vacancies in BS-12 provided more active sites, (2) BS-12 with sulfur vacancies acted as a co-catalyst to accelerate the hydrogen production rate, and (3) the piezoelectric field eliminated the electrostatic shielding and offered an additional driving force, which effectively promoted the separation of electron-hole pairs. This research clearly reveals the synergistic effect between piezocatalysis and photocatalysis as well as offers a promising sight for the rational design of high-efficiency piezo-photocatalysts.

Rational Design of Polymeric mRNA Delivery Vectors to Achieve Excellent Room-Temperature Storage Stability and Delivery Efficiency

Rational Design of Polymeric mRNA Delivery Vectors to Achieve Excellent Room-Temperature Storage Stability and Delivery Efficiency

Π‐Bridge Modulations in D–π–A Conjugated Microporous Polymers to Facilitate Charge Separation and Transfer Kinetics for Efficient Photocatalysis

AbstractThe burgeoning field of conjugated microporous polymers (CMPs) has generated widespread interest due to their potential as photocatalysts for hydrogen production from water. Nevertheless, their photocatalytic performance is sometimes hindered by inadequate charge separation and transfer, coupled with rapid charge recombination. Herein, a strategy to enhance photocatalytic performance via the customization of π‐bridges through the modulation of heteroatoms in a series of donor‐π‐acceptor (D‐π‐A) CMPs is proposed. This affords optimized energy levels and improved charge separation and transfer, thus boosting photocatalytic efficiency. Among various heteroatom substitutions, S‐doped CMP (10 mg) demonstrates the highest photocatalytic hydrogen evolution rate of 203 µmol h−1 (AQY450nm = 7.4%) under visible light irradiation. Subsequent experimental analysis reveals its superior photocatalytic performance can be largely related to its minimized exciton binding energy, facilitated charge transfer efficiency, and impeded charge recombination among these heteroatom‐doped D‐π‐A CMPs. This research paves the way for the rational design and modification of organic semiconductors for advanced solar‐driven photocatalysis by promoting charge separation and transfer.

Theoretical study on CO production mechanism from CO2 reduction on Cu–catalyst surface with different oxidation states

The rational design of copper (Cu)-based catalysts with different oxidation states is essential to achieve highly selective and efficient CO2 electroreduction. However, the effect of different oxide states of Cu-based catalysts has rarely been studied. Herein, the reaction mechanism of CO2 hydrogenation into CO on Cu-based catalysts with different oxidation states, such as Cu(111), Cu2O(111) and CuO(111), was studied using the density functional theory. The most favored pathway for CO production and the rate-controlling step on the three catalyst models were determined. The results show that, Cu2O (111) shows the best catalytic activity among the three catalysts due to the lowest activation barrier. The electronic structure analysis shows that Cu2O has the proper electronic structure to activate CO2 which is further reduced to CO. This work provides an important insight on the effect of oxidation state of Cu-based catalysts on the reduction of CO2 to CO.

Crystal epitaxy-confined Pd, Ti-bimetallic sites in the MFI zeolite for benzylalcohol oxidation.

A general strategy for confining Pd, Ti-bimetallic sites in the MFI zeolite by crystal epitaxy was developed. The tailored spatial intimacy of the bimetallic sites demonstrated distinct catalytic performance for the oxidation of benzylalcohol. The related mechanism was clarified and afforded a valuable pathway for rational catalyst design.

Redox-induced controllable engineering of MnO2-MnxCo3-xO4 interface to boost catalytic oxidation of ethane

Multicomponent oxides are intriguing materials in heterogeneous catalysis, and the interface between various components often plays an essential role in oxidations. However, the underlying principles of how the hetero-interface affects the catalytic process remain largely unexplored. Here we report a unique structure design of MnCoOx catalysts by chemical reduction, specifically for ethane oxidation. Part of the Mn ions incorporates with Co oxides to form spinel MnxCo3-xO4, while the rests stay as MnO2 domains to create the MnO2-MnxCo3-xO4 interface. MnCoOx with Mn/Co ratio of 0.5 exhibits an excellent activity and stability up to 1000 h under humid conditions. The synergistic effects between MnO2 and MnxCo3-xO4 are elucidated, in which the C2H6 tends to be adsorbed on the interfacial Co sites and subsequently break the C-H bonds on the reactive lattice O of MnO2 layer. Findings from this study provide valuable insights for the rational design of efficient catalysts for alkane combustion.

Reducing Overpotential of Lithium-Oxygen Batteries by Diatomic Metal Catalyst Orbital Matching Strategy.

Aprotic Li-O2 batteries have sparked attention in recent years due to their ultrahigh theoretical energy density. Nevertheless, their practical implementation is impeded by the sluggish reaction kinetics at the cathode. Comprehending the catalytic mechanisms is pivotal to developing efficient cathode catalysts for high-performance Li-O2 batteries. Herein, the intrinsic activity map of Li-O2 batteries is established based on the specific adsorption mode of O2 induced by diatomic catalyst orbital matching and the transfer-acceptance-backdonation mechanism, and the four-step screening strategy based on the intrinsic activity map is proposed. Guided by the strategy, FeNi@NC and FeCu@NC promising durable stability with a low overpotential are screened out from 27 Fe-Metal diatomic catalysts. Our research not only provides insights into the fundamental understanding of the reaction mechanism of Li-O2 batteries but also accelerates the rational design of efficient Li-O2 batteries based on the structure-activity relationship.

Transmission Electron Microscopic and X-ray Diffraction Based Study of Crystallographic Bibliography Demonstrated on Silver, Copper and Titanium Nanocrystals: State of the Art Statical Review

This statistical review compares the crystallographic structures of functional nanocrystals composed of silver (Ag), copper (Cu) and titanium (Ti) using transmission electron microscopy (TEM) and X-ray diffraction (XRD) analyses. TEM provides high-resolution imaging to directly visualize individual nanoparticles' size, internal shape and crystallinity. Statistical analysis quantifies variations in lattice parameters, crystal structure, size distributions, phase compositions, lattice strains, preferred orientation and lattice volume of these three crystalline nanomaterials. The review highlights the complementary roles of TEM and XRD in comprehensive Ag, Cu and Ti nanocrystalline materials characterization. The crystallographic functional parameters of Ag were 2θ= 38.1° (111), 44.3° (200) and 64.4° (220); for Cu crystal 43.3° (111), 50.4° (200), 74.1° (220), 89.9° (311) and 95.1° (222) and 35.1° (100), 38.4° (002), 40.2° (101), 53.0° (102), 63.0° (103), 70.7° (110), 76.2° (112), 82.3° (201) demonstrated for Ti nanocrystals. The crystallographic predominant plane or Miller indices were also revealed by selected area electron diffraction (SAED) on TEM. The FCC structure of Ag and Cu is shown in larger lattice volumes compared to the HCP structure of Ti and prefer oriented. The degree of crystallinity of Ti, Cu and Ag nanocrystalline materials was observed at 90.0%, 98.0% and 100.0% respectively. This quantitative comparison provides valuable insights into the structural property relationships in these nanocrystals, enabling rational design strategies for optimizing their performance in various functional applications.

Molecular dissection of the pseudokinase ZED1 expands effector recognition to the tomato immune receptor ZAR1.

The highly conserved angiosperm immune receptor HOPZ-ACTIVATED RESISTANCE 1 (ZAR1) is a bacterial pathogen recognition hub that mediates resistance by guarding host kinases for modification by pathogen effectors. The pseudokinase HOPZ-ETI DEFICIENT 1 (ZED1) is the only known ZAR1-guarded protein that interacts directly with a pathogen effector, HopZ1a, from the bacterial pathogen Pseudomonas syringae, making it a promising system for rational design of effector recognition for plant immunity. Here, we conducted an in-depth molecular analysis of ZED1. We generated a library of 164 random ZED1 mutants and identified 50 mutants that could not recognize the effector HopZ1a when transiently expressed in Nicotiana benthamiana. Based on our random mutants, we generated a library of 27 point mutants and found evidence of minor functional divergence between Arabidopsis (Arabidopsis thaliana) and N. benthamiana ZAR1 orthologs. We leveraged our point mutant library to identify regions in ZED1 critical for ZAR1 and HopZ1a interactions and identified two likely ZED1-HopZ1a binding conformations. We explored ZED1 nucleotide and cation binding activity and showed that ZED1 is a catalytically dead pseudokinase, functioning solely as an allosteric regulator upon effector recognition. We used our library of ZED1 point mutants to identify the ZED1 activation loop regions as the most likely cause of interspecies ZAR1-ZED1 incompatibility. Finally, we identified a mutation that abolished ZAR1-ZED1 interspecies incompatibility while retaining the ability to mediate HopZ1a recognition, which enabled recognition of HopZ1a through tomato (Solanum lycopersicum) ZAR1. This provides an example of expanded effector recognition through a ZAR1 ortholog from a non-model species.