Search Results (135)

Background/Objectives: Increasing the solid-state landscape of an active pharmaceutical ingredient (API) by generating new crystalline forms (e.g., polymorphs, cyclodextrin (CD) inclusion complexes, co-crystals, and salts) can yield products with significantly enhanced biopharmaceutical properties (especially increased water solubility), thereby improving API delivery and extending its lifetime. The aim of this study was the isolation of new solid forms of the poorly water-soluble non-steroidal anti-inflammatory drug fenbufen (FBF), for which relatively few solid phases have been reported to date. Further motivation for the study is the recent finding that it has potential for repurposing to treat acute pancreatitis. Methods: Interventions for generating new solid forms of FBF included (a) polymorph screening with a variety of solvent media, (b) attempts to form solid inclusion complexes with the native cyclodextrins α-, β-, and γ-CD using various preparative methods, and (c) co-crystallization with a series of coformers to produce co-crystals and/or molecular salts. Results: No new polymorphic forms of FBF were identified, but screening with CDs resulted in isolation and characterization of a new solid inclusion complex with γ-CD. However, co-crystallization of FBF with the water-soluble coformer isonicotinamide yielded two new products, namely a 1:1 co-crystal and an unusual multi-component ionic co-crystal, whose aqueous solubility indicated significant enhancement of FBF solubility. Conclusions: Due to its extremely low water solubility, FBF presented challenges during the study aimed at modifying its crystalline form. However, two new supramolecular forms, a co-crystal and an ionic co-crystal, were isolated, the latter phase having potential for further formulation owing to its significantly enhanced solubility. Full article

A nitro-derivative of fenamic acid (4′–nitro–fenamic acid) was synthesized and used as ligand for the synthesis of four Co(II) complexes in the absence or presence of the N,N′-donors 2,2′–bipyridylamine, 1,10–phenanthroline and 2,9–dimethyl–1,10–phenanthroline. The characterization of the resultant complexes was performed with diverse techniques (elemental analysis, molar conductivity measurements, IR and UV-vis spectroscopy, single-crystal X-ray crystallography). The biological evaluation of the compounds encompassed (i) antioxidant activity via hydrogen peroxide (H₂O₂) reduction and free radical scavenging; (ii) antimicrobial screening against two Gram-positive and two Gram-negative bacterial strains; (iii) interactions with calf-thymus (CT) DNA; (iv) cleavage of supercoiled pBR322 plasmid DNA (pDNA), in the dark or under UVA/UVB/visible light irradiation; and (v) binding affinity towards bovine and human serum albumins. The antioxidant activity of the compounds against 2,2′–azinobis–(3–ethylbenzothiazoline–6–sulfonic acid) radicals and H₂O₂ is significant, especially in the case of H₂O₂. The complexes exhibit adequate antimicrobial activity against the strains tested. The complexes interact with CT DNA through intercalation with binding constants reaching a magnitude of 10⁶ M⁻¹. The compounds have a significantly enhanced pDNA-cleavage ability under irradiation, showing promising potential as photodynamic therapeutic agents. All compounds can bind tightly and reversibly to both albumins tested. Full article

Microbially induced carbonate precipitation (MICP) is the precipitation of CaCO₃ crystals, induced by microbial metabolic activities such as ureolysis. Various applications of MICP have been proposed as innovative biocementation techniques. This study aimed to verify the feasibility of ureolysis-driven MICP applications in deep-subsurface environments (e.g., enhanced oil recovery and geological carbon sequestration). To this end, we screened sludge collected from a high-temperature anaerobic digester for facultatively anaerobic thermophilic bacteria possessing ureolytic activity. Then, we examined the ureolysis-driven MICP using a representative isolate, Bacillus haynesii strain SK1, under aerobic, anoxic, and strict anaerobic conditions at 30 °C, 40 °C, and 50 °C. All cultures showed ureolysis and the formation of insoluble precipitates. Fourier transform infrared spectroscopy analysis revealed precipitates comprising CaCO₃ at 30 °C, 40 °C, and 50 °C under aerobic conditions but only at 50 °C under anoxic and strict anaerobic conditions, suggesting efficient MICP at 50 °C. Interestingly, an X-ray diffraction analysis indicated that calcium carbonate crystals that were produced under aerobic conditions were in the form of calcite, while those that were produced under anoxic and strict anaerobic conditions at 50 °C were mostly in the form of vaterite. Thus, we demonstrated ureolysis-driven MICP under high-temperature and O₂-depletion conditions, suggesting the potential of MICP applications in deep-subsurface environments. Full article

Nuclear factor-κB (NF-κB) signaling plays a pivotal role in regulating immune responses and is strongly implicated in cancer progression and inflammation-related diseases. The inhibitory κB kinases (IKKs), particularly IKKα, are central to modulating NF-κB activity, with distinct roles in the canonical and non-canonical signaling pathways. This study investigates the potential of selectively targeting IKKα to develop novel therapeutic strategies. A receptor–ligand interaction pharmacophore model was generated based on the co-crystallized structure of IKKα, incorporating six key features, two hydrogen bond acceptors, two hydrogen bond donors, one hydrophobic region, and one hydrophobic aromatic region. This model was used to virtually screen a diverse natural compound library of 5540 molecules, yielding 82 candidates that matched the essential pharmacophore features. Molecular docking and molecular dynamics simulations were subsequently employed to evaluate binding conformations, stability, and dynamic behavior of the top hits. The end-state free energy calculations (gmx_MMPBSA) further validated the interaction strength and stability of selected compounds. To experimentally confirm their inhibitory potential, key compounds were tested in LPS-stimulated RAW 264.7 cells, where they significantly reduced IκBα phosphorylation. These findings validate the integrative computational-experimental approach and identify promising natural compounds as selective IKKα inhibitors for further therapeutic development in cancer and inflammatory diseases. Full article

In this study, the nano-spinel CoMn₂O₄ was synthesized by coprecipitation pyrolysis and employed to heterogeneously activate hypochlorite (NaClO) for the oxidative decolorization of methylene blue (MB). The crystal structure, elemental composition, surface morphology, and microstructure of the prepared CoMn₂O₄ nano-spinel were analyzed using a series of characterization techniques. The pyrolysis temperature was screened on the basis of MB decolorization efficiency and the leaching of metal ions during the reaction. The MB decolorization efficiency was compared using different catalysts and process. The impacts of CoMn₂O₄ dosage, effective chlorine dose, MB concentration, and initial pH on MB decolorization were explored. The catalytic mechanism of MB oxidation was elucidated through quenching experiments combined with radical identification. The degradation pathway of MB was preliminarily proposed based on the detection of the intermediates. The reusability of recycled CoMn₂O₄ was finally investigated. The results revealed that maximal MB oxidation efficiency and minimal leaching of Co and Mn ions were achieved at the calcination temperature of 600 °C. Complete oxidative decolorization of MB within 40 min was obtained at an initial MB concentration of 50 mg/L, a CoMn₂O₄ dosage of 1 g/L, an effective chlorine dose of 0.1%, and an initial pH of 4.3. Superoxide radical (O₂^•−) was found to be dominantly responsible for MB decolorization according to the results of radical scavenging experiments and electron paramagnetic resonance. The CoMn₂O₄ spinel can be recycled for five cycles with the MB removal in the range of 90.6~98.7%. Full article

The main priority in leishmaniasis-endemic countries is to find safer and more accessible treatments for this neglected disease. In this study, we focus on a drug repositioning strategy using molecular docking. New molecular entities (NMEs) approved by the FDA from 2019 to the present were analyzed. The therapeutic target was the sterol 14-alpha demethylase from Leishmania infantum. Of the 125 NMEs tested, 16 demonstrated greater affinity in virtual screening than the co-crystallized inhibitor (fluconazole). This approach offers a promising method for identifying new uses for existing drugs and provides a rapid way to discover safer treatments for leishmaniasis. Full article

Background: During the dissolution of amorphous solid dispersion (ASD) formulations, the drug load (DL) often impacts the release mechanism and the occurrence of loss of release (LoR). The ASD/water interfacial gel layer and its specific phase behavior in connection with DL strongly dictate the release mechanism and LoR of ASDs, as reported in the literature. Thermodynamically driven liquid-liquid phase separation (LLPS) and/or drug crystallization at the interface are the key phase transformations that drive LoR. Methods: In this study, a combination of Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) thermodynamic modeling and in silico molecular simulation was applied to investigate the release mechanism and the occurrence LoR of an ASD formulation consisting of ritonavir as the active pharmaceutical ingredient (API) and the polymer, polyvinylpyrrolidone-co-vinyl acetate (PVPVA64). A thermodynamically modeled ternary phase diagram of ritonavir (PVPVA64) and water was applied to predict DL-dependent LLPS in the ASD/water interfacial gel layer. Microscopic Erosion Time Testing (METT) was used to experimentally validate the phase diagram predictions. Additionally, in silico molecular simulation was applied to provide further insights into the phase separation, the release mechanism, and aggregation behavior on a molecular level. Results: Thermodynamic modeling, molecular simulation, and experimental results were consistent and complementary, providing evidence that ASD/water interactions and phase separation are essential factors driving the dissolution behavior and LoR at 40 wt% DL of the investigated ritonavir/PVPVA64 ASD system, consistent with previous studies. Conclusions: This study provides insights into the potential of blending thermodynamic modeling, molecular simulation, and experimental research to comprehensively understand ASD formulations. Such a combined approach can be leveraged as a computational framework to gain insights into the ASD dissolution mechanism, thereby facilitating in silico screening, designing, and optimization of formulations with the benefit of significantly reducing the number of experimental tests. Full article

Although the primary pandemic of SARS-CoV-2 is over, there are concerns about the resurgence of the next wave of related viruses, including a wide range of variant viruses. The soluble ACE2 (sACE2) inhibits the SARS-CoV-2 spike protein ACE2 interaction and has potential as a variant-independent therapeutic against SARS-CoV-2. Here, we introduce novel disulfide bonds in the wild-type sACE2-Fc by structure-guided mutagenesis, aiming to improve its stability. The stability of each mutant was assessed by a thermal shift assay to screen mutants with increased thermal stability. As a result, we identified a mutant sACE2-Fc with a significantly increased melting temperature. X-ray crystal structure determination of the sACE2 mutant confirmed the correct formation of the designed disulfide bond, and there were no significant structural disturbances. We also proved that the thermostable sACE2-Fc preserved the spike protein binding affinity comparable to the wild-type sACE2-Fc in both molecular and cellular environments, suggesting its therapeutic potential. Full article

The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1, we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition. Full article

Under simulated conditions typical of a high-temperature, high-pressure (HTHP) oil and gas reservoir in the South China Sea, dynamic corrosion evaluation experiments were performed on a three-layer screen structure and three types of sand retaining media. The results showed significant variations in corrosion morphology and rates among different screen components and materials. Corrosion products on the base pipe accumulated as cubic crystals, while the protective shroud showed surface needle-like corrosion products. Sand retaining media exhibited “coiled wire” corrosion products with cubic accumulations along seam edges. The 316L media showed a high corrosion risk, especially at temperatures between 140–150 °C. As CO₂ partial pressure increased, corrosion rates generally rose. A new predictive method was developed to assess and compare the corrosion resistance and life of screens, achieving a compliance rate of over 90%. This method supports evaluating the corrosion life of screens in HTHP environments. For a typical well in the South China Sea gas field with 4% CO₂, there is a high risk of screen corrosion. The screen media was identified as a failure site with a minimum corrosion life of about 5 years, while the protective shroud’s life was estimated at 11–12 years. Full article

The Hippo pathway controls organ size and homeostasis and is linked to numerous diseases, including cancer. The transcriptional enhanced associate domain (TEAD) family of transcription factors acts as a receptor for downstream effectors, namely yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which binds to various transcription factors and is essential for stimulated gene transcription. YAP/TAZ-TEAD facilitates the upregulation of multiple genes involved in evolutionary cell proliferation and survival. TEAD1–4 overexpression has been observed in different cancers in various tissues, making TEAD an attractive target for drug development. The central drug-accessible pocket of TEAD is crucial because it undergoes a post-translational modification called auto-palmitoylation. Crystal structures of the C-terminal TEAD complex with small molecules are available in the Protein Data Bank, aiding structure-based drug design. In this study, we utilized the fragment molecular orbital (FMO) method, molecular dynamics (MD) simulations, shape-based screening, and molecular mechanics–generalized Born surface area (MM-GBSA) calculations for virtual screening, and we identified a novel non-covalent inhibitor—BC-001—with IC₅₀ = 3.7 μM in a reporter assay. Subsequently, we optimized several analogs of BC-001 and found that the optimized compound BC-011 exhibited an IC₅₀ of 72.43 nM. These findings can be used to design effective TEAD modulators with anticancer therapeutic implications. Full article

The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of −9.1, −8.9, and −8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (−9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants. Full article

The solid electrolyte Li₁₀GeP₂S₁₂ (LGPS) plays a crucial role in the development of all-solid-state batteries and has been widely studied both experimentally and theoretically. The properties of solid electrolytes, such as thermodynamic stability, conductivity, band gap, and more, are closely related to their ground-state structures. However, the presence of site-disordered co-occupancy of Ge/P and defective fractional occupancy of lithium ions results in an exceptionally large number of possible atomic configurations (structures). Currently, the electrostatic energy criterion is widely used to screen favorable candidates and reduce computational costs in first-principles calculations. In this study, we employ the machine learning- and active-learning-based LAsou method, in combination with first-principles calculations, to efficiently predict the most stable configuration of LGPS as reported in the literature. Then, we investigate the diffusion properties of Li ions within the temperature range of 500–900 K using ab initio molecular dynamics. The results demonstrate that the atomic configurations with different skeletons and Li ion distributions significantly affect the Li ions’ diffusion. Moreover, the results also suggest that the LAsou method is valuable for refining experimental crystal structures, accelerating theoretical calculations, and facilitating the design of new solid electrolyte materials in the future. Full article

To aid cocrystal screening, a deep forest-based cocrystal prediction model was developed in this study using data from the Cambridge Structural Database (CSD). The positive samples in the experiment came from the CSD. The negative samples were partly from the failure records in other papers, and some were randomly generated according to specific rules, resulting in a total of 8576 pairs. Compared with the models of traditional machine learning methods and simple deep neural networks models, the deep forest model has better performance and faster training speed. The accuracy is about 95% on the test set. Febuxostat cocrystal screening was also tested to verify the validity of the model. Our model correctly predicted the formation of cocrystal. It shows that our model is practically useful in practice. Full article

Coleus forskohlii (Willd.) Briq. is a medicinal herb of the Lamiaceae family. It is native to India and widely present in the tropical and sub-tropical regions of Egypt, China, Ethiopia, and Pakistan. The roots of C. forskohlii are edible, rich with pharmaceutically bioactive compounds, and traditionally reported to treat a variety of diseases, including inflammation, respiratory disorders, obesity, and viral ailments. Notably, the emergence of viral diseases is expected to quickly spread; consequently, these data impose a need for various approaches to develop broad active therapeutics for utilization in the management of future viral infectious outbreaks. In this study, the naturally occurring labdane diterpenoid derivative, Forskolin, was obtained from Coleus forskohlii. Additionally, we evaluated the antiviral potential of Forskolin towards three viruses, namely the herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), hepatitis A virus (HAV), and coxsackievirus B4 (COX-B4). We observed that Forskolin displayed antiviral activity against HAV, COX-B4, HSV-1, and HSV-2 with IC₅₀ values of 62.9, 73.1, 99.0, and 106.0 μg/mL, respectively. Furthermore, we explored the Forskolin’s potential antiviral target using PharmMapper, a pharmacophore-based virtual screening platform. Forskolin’s modeled structure was analyzed to identify potential protein targets linked to its antiviral activity, with results ranked based on Fit scores. Cathepsin L (PDB ID: 3BC3) emerged as a top-scoring hit, prompting further exploration through molecular docking and MD simulations. Our analysis revealed that Forskolin’s binding mode within Cathepsin L’s active site, characterized by stable hydrogen bonding and hydrophobic interactions, mirrors that of a co-crystallized inhibitor. These findings, supported by consistent RMSD profiles and similar binding free energies, suggest Forskolin’s potential in inhibiting Cathepsin L, highlighting its promise as an antiviral agent. Full article