Rational Design of Lipid Nanoparticles for Enhanced mRNA Vaccine Delivery via Machine Learning.

Since the coronavirus pandemic, mRNA vaccines have revolutionized the field of vaccinology. Lipid nanoparticles (LNPs) are proposed to enhance mRNA delivery efficiency; however, their design is suboptimal. Here, a rational method for designing LNPs is explored, focusing on the ionizable lipid composition and structural optimization using machine learning (ML) techniques. A total of 213 LNPs are analyzed using random forest regression models trained with 314 features to predict the mRNA expression efficiency. The models, which predict mRNA expression levels post-administration of intradermal injection in mice, identify phenol as the dominant substructure affecting mRNA encapsulation and expression. The specific phospholipids used as components of the LNPs, as well as the N/P ratio and mass ratio, are found to affect the efficacy of mRNA delivery. Structural analysis highlights the impact of the carbon chain length on the encapsulation efficiency and LNP stability. This integrated approach offers a framework for designing advanced LNPs and has the potential to unlock the full potential of mRNA therapeutics.

Structural modifications toward improved lead-203/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors.

PURPOSE: The lead-203 (203Pb)/lead-212 (212Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that 212Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr3-octreotide (TOC)-based radiopharmaceuticals. METHODS: New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of 203Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the 203Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG2-TOC), which was then further evaluated for efficacy in 212Pb therapy studies. RESULTS: The lead radiopeptide drug conjugate (RPDC) - [203Pb]Pb-PSC-PEG2-TOC - significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [203Pb]Pb-DOTA0-Tyr3-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [212Pb]Pb-PSC-PEG2-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [212Pb]Pb-PSC-PEG2-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model. CONCLUSION: Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of 203/212Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG2-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.

Recent Progress of the Cathode Material Design for Aqueous Zn-Organic Batteries.

Aqueous zinc-ion batteries (ZIBs) have emerged as the most promising candidate for large-scale energy storage due to their inherent safety, environmental friendliness, and cost-effectiveness. Simultaneously, the utilization of organic electrode materials with renewable resources, environmental compatibility, and diverse structures has sparked a surge in research and development of aqueous Zn-organic batteries (ZOBs). A comprehensive review is warranted to systematically present recent advancements in design principles, synthesis techniques, energy storage mechanisms, and zinc-ion storage performance of organic cathodes. In this review article, we comprehensively summarize the energy storage mechanisms employed by aqueous ZOBs. Subsequently, we categorize organic cathode materials into small-molecule compounds and high-molecular polymers respectively. Novel polymer materials such as conjugated polymers (CPs), conjugated microporous polymers (CMPs), and covalent organic frameworks (COFs) are highlighted with an overview of molecular design strategies and structural optimization based on organic cathode materials aimed at enhancing the performance of aqueous ZOBs. Finally, we discuss the challenges faced by aqueous ZOBs along with future prospects to offer insights into their practical applications.

A novel approach to exploit Small-Molecule glucagon-like Peptide-1 receptor agonists with high potency.

Small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonists are recognized as promising therapeutics for type 2 diabetes mellitus (T2DM) and obesity. Danuglipron, an investigational small-molecule agonist, has demonstrated high efficacy in clinical trials. However, further development of danuglipron is challenged by a high rate of gastrointestinal adverse events. While these effects may be target-related, it is plausible that the carboxylic acid group present in danuglipron may also play a role in these outcomes by affecting the pharmacokinetic properties and dosing regimen of danuglipron, as well as by exerting direct gastrointestinal irritation. Therefore, this study aims to replace the problematic carboxylic acid group by exploring the internal binding cavity of danuglipron bound to GLP-1R using a water molecule displacement strategy. A series of novel triazole-containing compounds have been designed and synthesized during the structure-activity relationship (SAR) study. These efforts resulted in the discovery of compound 2j with high potency (EC50 = 0.065 nM). Moreover, docking simulations revealed that compound 2j directly interacts with the residue Glu387 within the internal cavity of GLP-1R, effectively displacing the structural water previously bound to Glu387. Subsequent in vitro and in vivo experiments demonstrated that compound 2j had comparable efficacy to danuglipron in enhancing insulin secretion and improving glycemic control. Collectively, this study offers a practicable approach for the discovery of novel small-molecule GLP-1R agonists based on danuglipron, and compound 2j may serve as a lead compound to further exploit the unoccupied internal cavity of danuglipron's binding pocket.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.

How digital transformation facilitate synergy for pollution and carbon reduction: Evidence from China.

Frontier studies have neglected the impact of digital transformation (DT) on the synergy for pollution and carbon reduction (SPCR) from the perspective of micro enterprises. This paper explores the SPCR effect of DT, as well as its mechanism at micro-firm level. The study found that: (1) DT significantly facilitates corporate SPCR. For every 10% increase in the level of DT, the ranking of SPCR will rise by about 2.3 places. This effect is more obvious in high-tech firms and non-heavy polluters, firms in the eastern region in China, and non-SOE. (2) DT creates innovation-driven and structure-optimizing effects, which enhance the corporate green innovation ability, optimize the business structure and capital allocation structure of enterprises, and then drive the SPCR. (3) External public environmental concerns (PEC) and internal corporate ESG governance act as "accelerators" promoting the SPCR effect of DT. Based on these, policy implications are made to accelerate the pace of corporate DT, give full play to the first-mover advantage, and break the "pollution (carbon) lock-in" with a view to providing theoretical references for the listed enterprises' digitalized governance of SPCR, as well as the governmental departments' formulation of relevant guiding policies, and striving to achieve the high-quality development goal.

Discovery and optimization of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel phosphodiesterase 4 inhibitors.

Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC50 of 4.78 ± 0.08 µM). And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC50 of 0.48 ± 0.02 µM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future.

Discovery and optimization of 3-(indolin-5-yloxy)pyridin-2-amine derivatives as potent necroptosis inhibitors.

Necroptosis is a form of regulated necrotic cell death and has been confirmed to play pivotal roles in the pathogenesis of multiple autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis. The development of necroptosis inhibitors may offer a promising therapeutic strategy for the treatment of these autoimmune diseases. Herein, starting from the in-house hit compound 1, we systematically performed structural optimization to discover potent necroptosis inhibitors with good pharmacokinetic profiles. The resulting compound 33 was a potent necroptosis inhibitor for both human I2.1 cells (IC50 < 0.2 nM) and murine Hepa1-6 cells (IC50 < 5 nM). Further target identification revealed that compound 33 was an inhibitor of receptor interacting protein kinase 1 (RIPK1) with favorable selectivity. In addition, compound 33 also exhibited favorable pharmacokinetic profiles (T1/2 = 1.32 h, AUC = 1157 ng·h/mL) in Sprague-Dawley rats. Molecular docking and molecular dynamics simulations confirmed that compound 33 could bind to RIPK1 with high affinity. In silico ADMET analysis demonstrated that compound 33 possesses good drug-likeness profiles. Collectively, compound 33 is a promising candidate for antinecroptotic drug discovery.

Structural Optimization and Performance of a Low-Frequency Double-Shell Type-IV Flexural Hydroacoustic Transducer.

To amplify the displacement of the radiation shell, a double-shell type-IV curved hydroacoustic transducer was proposed. Through Ansys finite element simulation, the vibration modes of the transducer in different stages and the harmonic response characteristics in air and water were studied, and the bandwidth emission of the hydroacoustic transducer was achieved. By optimizing the size of each component, the resonant frequency of the transducer is 740 Hz, the maximum conductivity was 0.66 mS, and the maximum transmitting voltage response was 130 dB. According to the optimized parameters, a longitudinal acoustic transducer prototype was manufactured, and a physical test was conducted in an anechoic pool. The obtained resonant frequency was 750 Hz, the maximum conductivity was 0.44 mS, the maximum transmitting voltage response was 129.25 dB, and the maximum linear dimension was 250 mm, which match the simulated value of the virtual prototype and meet the expected requirements.

Numerical Study and Structural Optimization of Water-Wall Temperature-Measurement Device for Ultra-Supercritical Boiler.

The temperature of the water wall in the furnace chamber is extremely important for the daily operation of a boiler. Considering the high temperature and dusty environment in the furnace, a temperature measurement device mainly composed of four parts (armored temperature sensor, in-furnace heat-collecting block, out-furnace fixing base, and protective cannula) was designed in this study, which could be used to directly obtain the temperature of the in-furnace water-wall. Numerical simulations of temperature measurement devices with different heat-collecting block structures were carried out using the computer fluid dynamics method. After comparing the measurement accuracy and considering the practical application scenarios, the optimized heat-collecting block structure with a specific expansion gap (0.5 mm wide and 4 mm deep) was selected for practical application. Such a temperature measurement device was then applied to a 1000 MW ultra-supercritical coal-fired boiler in China, and the tested in-furnace water-wall temperature data were in good agreement with relevant research. Compared with the conventional temperature measurement device arranged outside the furnace, the in-furnace water-wall temperature-measurement device adopted in this study has a more sensitive response characteristic and can directly reflect the temperature of the water wall inside the furnace. In addition, it can also reflect the local slag formation state of the water wall and has a long service life.

Design, Synthesis, and Evaluation of B-(Trifluoromethyl)phenyl Phosphine-Borane Derivatives as Novel Progesterone Receptor Antagonists.

We previously revealed that phosphine-boranes can function as molecular frameworks for biofunctional molecules. In the present study, we exploited the diversity of available phosphines to design and synthesize a series of B-(trifluoromethyl)phenyl phosphine-borane derivatives as novel progesterone receptor (PR) antagonists. We revealed that the synthesized phosphine-borane derivatives exhibited LogP values in a predictable manner and that the P-H group in the phosphine-borane was almost nonpolar. Among the synthesized phosphine-boranes, which exhibited PR antagonistic activity, B-(4-trifluoromethyl)phenyl tricyclopropylphosphine-borane was the most potent with an IC50 value of 0.54 µM. A docking simulation indicated that the tricyclopropylphosphine moiety plays an important role in ligand-receptor interactions. These results support the idea that phosphine-boranes are versatile structural options in drug discovery, and the developed compounds are promising lead compounds for further structural development of next-generation PR antagonists.

Structural Optimization, Fungicidal Activities Evaluation, DFT Study and Structure-Activity Relationship of Dopamine Derivatives with Benzothiazole Fragment from Polyrhachis dives.

In our previous work, two dopamine derivatives with benzothiazole fragment were isolated and identified from Polyrhachis dives (P. dives). Based on their characteristic structure, we used them as lead compound to carry out structural optimization and subsequent fungicidal evaluation. Here 20 dopamine derivatives with benzothiazole fragment were designed and synthesized by a facile method, and their structures were characterized by 1 H-NMR, 13 CNMR and HMRS. In bioassays, most of the title compounds possess potential fungicidal activities against Altenaia alternala (A. alternala) and Botrytis cinerea (B. cinerea). Especially, (E)-N-(2-(benzo[d]thiazol-6-yl)ethyl)-3-(p-tolyl)acrylamide and (E)-N-(2-(benzo[d]thiazol-6-yl)ethyl)-3-(4-(trifluoromethyl)phenyl)acrylamide displayed 29.3 mg/L and 10.7 mg/L EC50 value against A. alternala, respectively, which possessed equivalent fungicidal activities level to hymexazol.

Structural Optimization of BIPPO Analogs as Potent Antimalarials.

Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC50 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog 30 (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC50 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC50 > 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies.

The Discovery of Indole-2-carboxylic Acid Derivatives as Novel HIV-1 Integrase Strand Transfer Inhibitors.

As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 µM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

Discovery of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives as novel xanthine oxidase inhibitors.

A series of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their xanthine oxidase (XO) inhibitory activities. Among these compounds, 9m emerged as the most effective XO inhibitor with an IC50 value of 0.70 µM, which was approximately 14-fold more potent than allopurinol. Additionally, compound 9m displayed favorable drug-like properties with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.33 and 3.41, respectively. We further explored the binding mode of 9m in complex with XO by molecular docking and molecular dynamics studies. In vivo hypouricemic studies also suggested that 9m could effectively lower the serum uric acid levels of rat. In summary, compound 9m could be a promising lead for further development of XO inhibitors.

Stiffness optimization and reliable design of a hip implant by using the potential of additive manufacturing processes.

BACKGROUND: Due to the steadily increasing life expectancy of the population, the need for medical aids to maintain the previous quality of life is growing. The basis for independent mobility is a functional locomotor system. The hip joint can be so badly damaged by everyday wear or accelerated by illness that reconstruction by means of endoprostheses is necessary. RESULTS: In order to ensure a high quality of life for the patient after this procedure as well as a long service life of the prosthesis, a high-quality design is required, so that many different aspects have to be taken into account when developing prostheses. Long-term medical studies show that the service life and operational safety of a hip prosthesis by best possible adaptation of the stiffness to that of the bone can be increased. The use of additive manufacturing processes enables to specifically change the stiffness of implant structures. CONCLUSIONS: Reduced implant stiffness leads to an increase in stress in the surrounding bone and thus to a reduction in bone resorption. Numerical methods are used to demonstrate this fact in the hip implant developed. The safety of use is nevertheless ensured by evaluating and taking into account the stresses that occur for critical load cases. These results are a promising basis to enable longer service life of prostheses in the future.

Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation.

The colchicine binding site of tubulin is a promising target for discovering novel antitumor agents which exert the antiangiogenic effect and are not susceptible to multidrug resistance. For identifying novel tubulin inhibitors, structure-based virtual screening was applied to identify hit 9 which displayed moderate tubulin polymerization inhibition and broad-spectrum in vitro antitumor activity. Structural optimization was performed, and biological assay revealed analog E27 displayed the best antitumor activity with IC50 values ranging from 7.81 µM to 10.36 µM, and improved tubulin polymerization inhibitory activity (IC50 = 16.1 µM). It significantly inhibited cancer cell migration and invasion, induced cell apoptosis and arrested the cell cycle at G2/M phase. Moreover, the apoptotic effect of E27 is related to the increased ROS level, the decrease of MMP, and the abnormal expression of apoptosis-related proteins. Taken together, these results suggested E27 was a promising lead compound for discovering novel tubulin-targeted antitumor agents.

Structural optimizations and bioevaluation of N-substituted acridone derivatives as strong topoisomerase II inhibitors.

Previously, an array of N-substituted acridone derivatives have been reported as potent topoisomerase II (topo II) inhibitors, and preliminary structure-activity relationship (SAR) outcomes revealed that the linker between 1-NH and N-methyl piperazine motif of the tricyclic acridone scaffold significantly affected their anti-proliferative potencies. To further explore the SARs of acridone-derived topo II inhibitors, a wider range of novel acridone derivatives were herein synthesized via two rounds of structural optimizations on two validated hits, E17 and E24. Initially, the linker length was optimized, and then influences of N-methyl piperazinyl moiety and disposition of three N atoms on the bioactivity were investigated. As a result, a newly developed topo II inhibitor 6 h was found to be more potent than E17 and E24, thereby serving as a tool compound for the follow-up mechanistic study. Compound 6 h functioned as a strong topo IIα/ß inhibitor, caused obvious DNA damage, and induced apoptosis by triggering the loss of mitochondrial membrane potential (Δψm). Further molecular docking and MD study illustrated the favorable interactions of 6 h with both topo IIα and topo IIß subtypes.

Parameter Sensitivity Analysis of Mounting Pedestals and Multi-Objective Optimization for a Multi-Support Rigid Body System.

In this paper, a parameter sensitivity analysis of mounting pedestals and a multi-objective optimization design for vibration reduction in a multi-support rigid body system, taking an aeroengine-lubricating oil tank supported by multiple mounting pedestals as an example, are conducted based on the third version of non-dominated sorting genetic algorithm (NSGA-Ⅲ) combined with Sobol's sensitivity analysis method (SSAM). An aeroengine-lubricating oil tank with three mounting pedestals is simplified as a three-support dynamic system, and its dynamics model is established. Several structural parameters of mounting pedestals are taken as the design variables, and the system vibration response and the reaction force of the front and rear mounting pedestals are considered as the objective functions. The first-order results and total sensitivity index of different design parameters for each objective function are obtained via SSAM, and the five most sensitive parameters are selected. Based on the above five design parameters, multi-objective optimization designing for vibration reduction in a simplified lubricating oil tank system is conducted based on NSGA-Ⅲ, and the results of the above triple-objective optimization are obtained as a Pareto-front surface with an obvious frontier. It can be observed from the simulation results that the oil tank vibration of the optimized system is effectively suppressed under the unbalanced excitation of two typical engine speeds. The established method and the main results can provide guidance for designers of aeroengine external structural systems, which can help to achieve superior system dynamic performances in engineering applications.

Structural Optimization and Improving Antitumor Potential of Moreollic Acid from Gamboge.

Moreollic acid, a caged-tetraprenylated xanthone from Gamboge, has been indicated as a potent antitumor molecule. In the present study, a series of moreollic acid derivatives with novel structures were designed and synthesized, and their antitumor activities were determined in multifarious cell lines. The preliminary screening results showed that all synthesized compounds selectively inhibited human colon cancer cell proliferation. TH12-10, with an IC50 of 0.83, 1.10, and 0.79 µM against HCT116, DLD1, and SW620, respectively, was selected for further antitumor mechanism studies. Results revealed that TH12-10 effectively inhibited cell proliferation by blocking cell-cycle progression from G1 to S. Besides, the apparent structure-activity relationships of target compounds were discussed. To summarize, a series of moreollic acid derivatives were discovered to possess satisfactory antitumor potentials. Among them, TH12-10 displays the highest antitumor activities against human colon cancer cells, in which the IC50 values in DLD1 and SW620 are lower than that of 5-fluorouracil.