Cocrystal Prediction of Nifedipine Based on the Graph Neural Network and Molecular Electrostatic Potential Surface.

Nifedipine (NIF) is a dihydropyridine calcium channel blocker primarily used to treat conditions such as hypertension and angina. However, its low solubility and low bioavailability limit its effectiveness in clinical practice. Here, we developed a cocrystal prediction model based on Graph Neural Networks (CocrystalGNN) for the screening of cocrystals with NIF. And scoring 50 coformers using CocrystalGNN. To validate the reliability of the model, we used another prediction method, Molecular Electrostatic Potential Surface (MEPS), to verify the prediction results. Subsequently, we performed a second validation using experiments. The results indicate that our model achieved high performance. Ultimately, cocrystals of NIF were successfully obtained and all cocrystals exhibited better solubility and dissolution characteristics compared to the parent drug. This study lays a solid foundation for combining virtual prediction with experimental screening to discover novel water-insoluble drug cocrystals.

Evolution characteristics of micromechanics provides insights into the microstructure of pharmaceutical tablets fabricated by bimodal mixtures.

This research focuses on the evolution of mechanical behavior of bimodal mixtures undergoing compaction and diametrical compression. The clusters were built and discrete element method (DEM) was used to investigate the densification process and micromechanics of bimodal mixtures. Additionally, a more comprehensive investigate of the respective breakage of the bimodal mixtures has been carried out. On this basis, qualitative and quantitative analysis of the compressive force, force chain, contact bonds and density field evolution characteristics of the clusters are investigated during the compression process. The entire loading process of the clusters is divided into three stages: rearrangement, breakage and elastic-plastic deformation. Additionally, there are differences in the evolution of micromechanics behavior of different particles in the bimodal mixture, with pregelatinized starch breakage and deformation occurring before microcrystalline cellulose. With the tablet deformation, the fragmentation process of the tablet started at the point of contact and extended toward the center, and the curvature of the force chain increased. This approach may potentially hold a valuable new information relevant to important transformation forms batch manufacturing to advanced manufacturing for the oral solid dosage form.

A new methodology of understanding the mechanism of high shear wet granulation based on experiment and molecular dynamics simulation.

In high shear wet granulation (HSWG), the interaction mechanism between binder and powder with different sugar content is still unclear. Herein, the law and mechanism of the interaction between binder and powder were studied on the molecular level by combining experiment analysis through the Kriging model and molecular dynamics (MD) simulation. For the sticky powder with high sugar content, the ethanol in the binder played a pivotal role in dispersing water into powders, and the amount of water determined the growth of granules. In the saturating stage, the reduction of sugar content facilitates the penetration of ethanol molecules. The concentration of ethanol determines whether the mixture is blended uniformly in the merging stage. The simulation results are consistent with the actual situation and explain the competition mechanism of interaction with binder and powder. Therefore, this research offers an efficient strategy for the in-depth understanding of the HSWG process where the powder is sticky, as well as providing guidelines for the practical application of preparation for Traditional Chinese Medicine (TCM) granules.

Investigation of mixing homogeneity of binary particle systems in high-shear wet granulator by DEM.

To provide a theoretical foundation and a good understanding for the real manufacturing granulation process, this paper investigates the effect of particle properties on the mixing process in the high-shear wet granulator, a common equipment in one of the key technologies in the growth of the pharmaceutical industry that has rarely been used to examine particle mixing-related problems in previous numerical simulations. The discrete element method (DEM) and the relative standard deviation (RSD) to explore binary particle systems with a range of sizes, densities, and volume fractions, and measure the mixing homogeneity of the particles. Results show that, for binary particle systems, particle size, density, and volume fraction all significantly affect mixing homogeneity, with good mixing occurring for a single size and a 1:1 volume fraction for the same density. Similar Brazil nut effect and Reverse-Brazil nut effect occurrences were discovered for many particle systems at various stages. There is a size threshold for a given binary particle system. Then, in a binary system, particles of a single size and density had nearly similar vertical driving forces, and these forces may vary by up to 10 times with changes in size or density. In the end, granular temperature rises with radial position and reaches its highest point at the pelletizer's wall and the top of the impeller. Density has less of an impact on granule velocity fluctuation than size.

Protective effects of thiamine on Wickerhamomyces anomalus against ethanol stress.

Wickerhamomyces anomalus (W. anomalus) is widely reported in the brewing industry and has positive effects on the aromatic profiles of wines because of its unique physiological characteristics and metabolic features. However, the accumulation of ethanol during fermentation inhibits the growth of W. anomalus. Thiamine is involved in the response against various abiotic stresses in microorganisms. Therefore, we used transcriptomic and metabolomic analyses to study the effect of thiamine on ethanol-stressed W. anomalus. The results indicate that thiamine could alleviate the inhibitory effect of ethanol stress on the survival of W. anomalus. Differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) caused by the thiamine intervention were identified as oxidative phosphorylation through integrated transcriptomic and metabolomic analyses. In addition, ethanol treatment decreased the content of intracellular adenosine triphosphate (ATP), while thiamine partially alleviated this phenomenon. The present comprehensive transcriptional overview and metabolomic analysis provide insights about the mechanisms of thiamine protection on W. anomalus under ethanol stress and promote the potential applications of W. anomalus in the fermentation industry.

Analysis of the ethanol stress response mechanism in Wickerhamomyces anomalus based on transcriptomics and metabolomics approaches.

BACKGROUND: Wickerhamomyces anomalus (W. anomalus) is a kind of non-Saccharomyces yeast that has a variety of unique physiological characteristics and metabolic features and is widely used in many fields, such as food preservation, biomass energy, and aquaculture feed protein production. However, the mechanism of W. anomalus response to ethanol stress is still unclear, which greatly limits its application in the production of ethanol beverages and ethanol fuels. Therefore, we checked the effects of ethanol stress on the morphology, the growth, and differentially expressed genes (DEGs) and metabolites (DEMs) of W. anomalus. RESULTS: High concentrations of ethanol (9% ethanol and 12% ethanol) remarkably inhibited the growth of W. anomalus. Energy metabolism, amino acid metabolism, fatty acids metabolism, and nucleic acid metabolism were significantly influenced when exposing to 9% ethanol and 12% ethanolstress, which maybe universal for W. anomalus to response to different concentrations of ethanol stressl Furthermore, extracellular addition of aspartate, glutamate, and arginine significantly abated ethanol damage and improved the survival rate of W. anomalus. CONCLUSIONS: The results obtained in this study provide insights into the mechanisms involved in W. anomalus response to ethanol stress. Therefore, new strategies can be realized to improve the ethanol tolerance of W. anomalus through metabolic engineering.

Application of Multivariate Methods to Evaluate Differential Material Attributes of HPMC from Different Sources.

The aim of the present study is to achieve differential material attributes (DMAs) of hydroxypropyl methylcellulose (HPMC) with different viscosity grades (K4M, K15M, and K100M) from different manufacturers (Anhui Shanhe and Dow Chemical). Two kinds of multivariate methods, principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), were adopted. The physicochemical properties of HPMC were systematically investigated via various techniques (e.g., SEM, particle size detection, and SeDeM characterization). Data from 33 characterization variables were applied to the multivariate methods. The PCA and OPLS-DA results indicated the differences between the HPMC from two manufacturers by the common variables that include the tablet hardness (HD), tensile strength (TS), bulk density, interparticle porosity, Carr index, cohesion index, Hausner ratio, flowability, and the width of the particle size distribution (span). Interestingly, these variables showed a certain correlation with each other, supporting the characterization results. Except for these different variables of the HPMC obtained by multivariate analysis results, distinguishable shapes and surface morphologies also appeared between different sources. To sum up, the powder properties (particle size, surface topography, dimension, flowability, and compressibility) and the tablet properties (HD and TS) were recognized as the DMAs of HPMC samples. This work provided the multivariate methods for the physicochemical characterization of HPMC, with potential in the quality control and formulation development.

Metabolomics Deciphered Metabolic Reprogramming Required for Biofilm Formation.

Biofilm formation plays a key role in many bacteria causing infections, which mostly accounts for high-frequency infectious recurrence and antibiotics resistance. In this study, we sought to compare modified metabolism of biofilm and planktonic populations with UTI89, a predominant agent of urinary tract infection, by combining mass spectrometry based untargeted and targeted metabolomics methods, as well as cytological visualization, which enable us to identify the driven metabolites and associated metabolic pathways underlying biofilm formation. Surprisingly, our finding revealed distinct differences in both phenotypic morphology and metabolism between two patterns. Furthermore, we identified and characterized 38 differential metabolites and associated three metabolic pathways involving glycerolipid metabolism, amino acid metabolism and carbohydrate metabolism that were altered mostly during biofilm formation. This discovery in metabolic phenotyping permitted biofilm formation shall provide us a novel insight into the dissociation of biofilm, which enable to develop novel biofilm based treatments against pathogen causing infections, with lower antibiotic resistance.

Application of the SeDeM Expert System in Studies for Direct Compression Suitability on Mixture of Rhodiola Extract and an Excipient.

The SeDeM expert system is used to reveal direct compression (DC) suitability of the active ingredients and excipients in preformulation. In this study, the system was used to predict compressibility of rhodiola extract (RhE) and its mixture with excipients. The parameter index (IP), parameter profile index (IPP), and good compressibility index (IGC) of RhE mixtures with different fillers were investigated. The results showed that RhE and mixture with lactose or starch were not suitable for DC according to the values of IP, IPP, and IGC, which can be corrected by pregelatinized starch (P-STA). The quality of tablets corrected by P-STA all satisfied the USP monograph limit. The findings from this study showed that the system is a useful tool to predict DC suitability on the mixture of RhE and an excipient.

Mass spectrometry-derived systems biology technologies delineate the system's biochemical applications of siderophores.

Siderophores are chemically diverse secondary metabolites that primarily assist the host organisms to chelate iron. Siderophores are biosynthesized by many biological organisms, including bacteria, fungi, and plants and they are responsible for a variety of biological functions beyond capture iron. Thus, they could provide a novel understanding of host-pathogen interactions, plant physiology, disease pathogenesis, and drug development. However, knowledge gaps in analytical technologies, chemistry, and biology have severely impeded the applications of siderophores, and a new strategy is urgently needed to bridge these gaps. Mass spectrometry (MS) and associated technologies render unparalleled advantages in this niche in terms of high throughput, resolution, and sensitivity. Herein, this critical review briefly summarizes progress in the study of siderophores and specifically identifies MS-based novel strategies that attempt to mimic the complexity of siderophore systems in order to increase the applicability of these compounds in the scientific community. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 37:188-201, 2018.

Siderophore biosynthesis coordinately modulated the virulence-associated interactive metabolome of uropathogenic Escherichia coli and human urine.

Uropathogenic Escherichia coli (UPEC) growth in women's bladders during urinary tract infection (UTI) incurs substantial chemical exchange, termed the "interactive metabolome", which primarily accounts for the metabolic costs (utilized metabolome) and metabolic donations (excreted metabolome) between UPEC and human urine. Here, we attempted to identify the individualized interactive metabolome between UPEC and human urine. We were able to distinguish UPEC from non-UPEC by employing a combination of metabolomics and genetics. Our results revealed that the interactive metabolome between UPEC and human urine was markedly different from that between non-UPEC and human urine, and that UPEC triggered much stronger perturbations in the interactive metabolome in human urine. Furthermore, siderophore biosynthesis coordinately modulated the individualized interactive metabolome, which we found to be a critical component of UPEC virulence. The individualized virulence-associated interactive metabolome contained 31 different metabolites and 17 central metabolic pathways that were annotated to host these different metabolites, including energetic metabolism, amino acid metabolism, and gut microbe metabolism. Changes in the activities of these pathways mechanistically pinpointed the virulent capability of siderophore biosynthesis. Together, our findings provide novel insights into UPEC virulence, and we propose that siderophores are potential targets for further discovery of drugs to treat UPEC-induced UTI.

Siderophore Biosynthesis Governs the Virulence of Uropathogenic Escherichia coli by Coordinately Modulating the Differential Metabolism.

Urinary tract infections impose substantial health burdens on women worldwide. Urinary tract infections often incur a high risk of recurrence and antibiotic resistance, and uropathogenic E. coli accounts for approximately 80% of clinically acquired cases. The diagnosis of, treatment of, and drug development for urinary tract infections remain substantial challenges due to the complex pathogenesis of this condition. The clinically isolated UPEC 83972 strain was found to produce four siderophores: yersiniabactin, aerobactin, salmochelin, and enterobactin. The biosyntheses of some of these siderophores implies that the virulence of UPEC is mediated via the targeting of primary metabolism. However, the differential modulatory roles of siderophore biosyntheses on the differential metabolomes of UPEC and non-UPEC strains remain incompletely understood. In the present study, we sought to investigate how the differential metabolomes can be used to distinguish UPEC from non-UPEC strains and to determine the associated regulatory roles of siderophore biosynthesis. Our results are the first to demonstrate that the identified differential metabolomes strongly differentiated UPEC from non-UPEC strains. Furthermore, we performed metabolome assays of mutants with different patterns of siderophore deletions; the data revealed that the mutations of all four siderophores exerted a stronger modulatory role on the differential metabolomes of the UPEC and non-UPEC strains relative to the mutation of any single siderophore and that this modulatory role primarily involved amino acid metabolism, oxidative phosphorylation in the carbon fixation pathway, and purine and pyrimidine metabolism. Surprisingly, the modulatory roles were strongly dependent on the type and number of mutated siderophores. Taken together, these results demonstrated that siderophore biosynthesis coordinately modulated the differential metabolomes and thus may indicate novel targets for virulence-based diagnosis, therapeutics, and drug development related to urinary tract infections.