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Protein homeostasis is a tightly conserved process that is regulated through the ubiquitin proteasome system (UPS) in a ubiquitin-independent or ubiquitin-dependent manner. Over the past two decades, the proteasome has become an excellent therapeutic target through inhibition of the catalytic core particle, inhibition of subunits responsible for recognizing and binding ubiquitinated proteins, and more recently, through targeted protein degradation using proteolysis targeting chimeras (PROTACs). The majority of the developed inhibitors of the proteasome's core particle rely on gaining selectivity through binding interactions within the unprimed substrate channel. Although this has allowed for selective inhibitors and chemical probes to be generated for the different proteasome isoforms, much remains unknown about the interactions that could be harnessed within the primed substrate channel to increase potency or selectivity. Herein, we discuss small molecules that interact with the primed substrate pocket and how their differences may give rise to altered activity. Taking advantage of additional interactions with the primed substrate pocket of the proteasome could allow for the generation of improved chemical tools for perturbing or monitoring proteasome activity.

In this paper, the ionic liquids Met-1, Met-2, Asp-1 and Asp-2 were prepared by acid-base neutralization reactions with different molar ratios of amino acids (methionine and aspartic acid) and concentrated sulfuric acid as raw materials. Four ionic liquids were formulated into different concentrations of inhibitors, and their hydration inhibition and inhibition mechanism were investigated by anti-expansion experiment, linear swelling experiment and flocculation experiment. The results showed that when the molar ratio of aspartic acid to concentrated sulfuric acid was 1:1.5, which was named Asp-2, and the concentration of Asp-2 was 1.0%, the inhibitor achieved the best hydration inhibition performance on clay with 91.95% anti-swelling rate and 21.37% linear swelling rate. Infrared spectra (FT-IR) analysis, thermogravimetric analysis (TGA), and laser particle size analysis were used to investigate the inhibition mechanism of Asp-2. The results showed that the average particle size of the hydrated soil samples increased by 0.282 μm and the median particle size increased by 2.101 μm after the addition of Asp-2 inhibitor, indicating that Asp-2 inhibitor played a good inhibitory role in the drilling fluid. [ABSTRACT FROM AUTHOR]

Safety of using hydrogen as fuel in aerospace applications is closely connected with hydrogen explosion safety during its transportation and stockpiling at launch places. In this paper, preventing the detonation propagation in the mixtures of hydrogen with air due to accidental hydrogen releases is studied in numerical experiments. Another fuel - hydrocarbon propylene – is studied as an optional inhibitor to be added in a small volume quantity to hydrogen-air mixture. The dependence of detonation wave cellular structure on the content of inhibitor is studied for different fuel-air ratios. The results make it possible determining the content of inhibitor sufficient for preventing the detonation onset or destroying the existing detonation wave. • Preventing the detonation propagation in the mixtures of hydrogen with air is studied numerically. • Another fuel - hydrocarbon propylene – is studied as an optional inhibitor. • The dependence of detonation wave cellular structure on the content of inhibitor is studied for different fuel-air ratios. • The content of inhibitor sufficient for preventing the detonation onset or destroying the existing detonation wave. [ABSTRACT FROM AUTHOR]

Shale hydration and expansion during drilling can lead to wellbore instability, sticking, and frequent leakage accidents. To prevent these issues, an ionic liquid (IL) inhibitor solution was synthesized using DL‐alanine and 98% concentrated sulphuric acid as raw materials. The optimum composition and effect of the synthesized inhibitor in oilfield water‐based drilling fluids were evaluated through anti‐expansion, linear expansion rate, water washing resistance, and clay hydration dispersion experiments. The inhibition mechanism was investigated by thermogravimetric analysis, infrared spectroscopy, zeta potential, contact angle, and X‐ray diffraction analysis. The results show that the optimum IL consists of a 1:1 molar ratio of DL‐alanine to concentrated sulphuric acid synthesized under a reaction temperature and time of 70°C and 18 h, respectively. The resulting DL‐alanine IL exhibited the best inhibitory effect on the hydration, dispersion, and expansion of clay at a concentration of 0.5% in aqueous solution, and its linear expansion rate was only 18.49%. After adding a quantitative amount of clay to different concentrations of DL‐alanine IL aqueous solution, the expansion volume of the clay decreased and the water washing resistance significantly improved. These results provide a theoretical basis for improving the safety and efficiency of shale horizontal well drilling operations. [ABSTRACT FROM AUTHOR]

Enhancing oil recovery (EOR) through water flooding methods, including smart water injection, low salinity water injection, polymer injection, and surfactant injection has become a pivotal strategy for enhancing productivity. Despite their promising outcomes, these methods often encounter challenges such as scaling formation and deposition, impacting reservoir permeability and production rates. A comprehensive understanding of scaling formation is crucial for effective implementation of these methods. This article explores various scaling types prevalent in the field, examining key parameters (temperature, pressure, and pH) that influence scaling formation. Additionally, it presents a diverse range of inhibitors employing both chemical and mechanical methods to mitigate and prevent scaling, thus safeguarding reservoir performance. The efficiency of inhibitors is scrutinized concerning chemical composition and performance maintenance under different temperature and pressure conditions. This study serves as a valuable resource for researchers, engineers, and industry experts involved in the oil industry and reservoir management. By elucidating scaling mechanisms, delineating consequences, and offering extensive solutions, it enhances comprehension and provides a foundation for improving oil recovery strategies. The findings of this study contribute to a better understanding of scaling mechanisms, providing insights that can be applied to optimize oil recovery processes, mitigate reservoir challenges, and improve overall reservoir management strategies. [ABSTRACT FROM AUTHOR]

ABSTRACT Leucyl‐tRNA synthetase (LeuRS) is clinically validated molecular target for antibiotic development. Recently, we have reported several classes of small‐molecular inhibitors targeting aminoacyl‐adenylate binding site of Mycobacterium tuberculosis LeuRS with antibacterial activity. In this work, we performed in silico site‐directed mutagenesis of M. tuberculosis LeuRS synthetic site in order to identify the most critical amino acid residues for the interaction with substrate and prove binding modes of inhibitors. We carried out 20‐ns molecular dynamics (MD) simulations and used umbrella sampling (US) method for the calculation of the binding free energy (ΔGb) of leucyl‐adenylate with wild‐type and mutated forms of LeuRS. According to molecular modeling results, it was found that His89, Tyr93, and Glu660 are essential amino acid residues both for aminoacyl‐adenylate affinity and hydrogen bond formation. We have selected His89 for experimental site‐directed mutagenesis since according to our previous molecular docking results this amino acid residue was predicted to be important for inhibitor interaction in adenine‐binding region. We obtained recombinant mutant M. tuberculosis LeuRS H89A. Using aminoacylation assay we have found that the mutation of His89 to Ala in the active site of M. tuberculosis LeuRS results in significant decrease of inhibitory activity for compounds belonging to three different chemical classes—3‐phenyl‐5‐(1‐phenyl‐1H‐[1,2,3]triazol‐4‐yl)‐[1,2,4]oxadiazoles, N‐benzylidene‐N′‐thiazol‐2‐yl‐hydrazines, and 1‐oxo‐1H‐isothiochromene‐3‐carboxylic acid (4‐phenyl‐thiazol‐2‐yl)‐amide derivatives. Therefore, the interaction with His89 should be taken into account during further M. tuberculosis LeuRS inhibitors development and optimization. [ABSTRACT FROM AUTHOR]

Apoptosis is an evolutionarily conserved cell death pathway that plays a crucial role in maintaining tissue homeostasis, orchestrating organismal development, and eliminating damaged cells. Dysregulation of apoptosis can contribute to the pathogenesis of malignant tumors and neurodegenerative diseases. Anticancer drugs typically possess the capacity to induce apoptosis in tumor cells. The Bcl-2 protein family, consisting of 27 members in humans, serves as the key regulator of mitochondrial function. This family can be divided into two functional groups: anti-apoptotic proteins (e.g., Bcl-2, Bcl-xl, Mcl-1) and pro-apoptotic proteins (e.g., Bad, Bax). Mcl-1 exerts its function by binding pro-apoptotic Bcl-2 proteins thereby preventing apoptosis induction. Overexpression of Mcl-1 not only correlates closely with tumorigenesis but also associates significantly with resistance towards targeted therapy and conventional chemotherapy. Effective induction of apoptosis can be achieved through inhibition or interference with Mcl-1. Thus, this mini review discusses existing Mcl-1 inhibitors. [ABSTRACT FROM AUTHOR]

The ubiquitin‐conjugating E2 enzymes play a central role in ubiquitin transfer. Disruptions to the ubiquitin system are implicated in multiple diseases, and as a result, molecules that modulate the activity of the ubiquitin system are of interest. E2 enzyme function relies on interactions with partner proteins, and the disruption of these is an effective way to modulate activity. Here, we report the discovery of ubiquitin variants (UbVs) that inhibit the E2 enzyme, Ube2d2 (UbcH5b). The six UbVs identified inhibit ubiquitin chain building, and the structural and biophysical characterisation of two of these demonstrate they bind to Ube2d2 with low micromolar affinity and high specificity. Both characterised UbVs bind at a site that overlaps with E1 binding, while the more inhibitory UbV has an additional binding site that blocks a critical non‐covalent ubiquitin‐binding site on the E2 enzyme. The discovery of novel protein‐based ubiquitin derivatives that inhibit protein–protein interactions is an important step towards discovering small molecules that inhibit the activity of E2 enzymes. Furthermore, the specificity of the UbVs within the Ube2d family suggests that it may be possible to develop tools to selectively inhibit highly related E2 enzymes. [ABSTRACT FROM AUTHOR]

Ferroptosis represents an iron- and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions. [ABSTRACT FROM AUTHOR]

Cerebroside sulfotransferase (CST) is considered as therapeutic target for substrate reduction therapy (SRT) for metachromatic leukodystrophy (MLD). The present study evaluates the therapeutic potential of 57 phytoconstituents of Withania somnifera against CST. Using binding score cutoff ≤-7.0 kcal/mol, top 10 compounds were screened and after ADME and toxicity-based screening, Withasomidienone, 2,4-methylene-cholesterol, and 2,3-Didehydrosomnifericin were identified as safe and potent drug candidates for CST inhibition. Key substrate binding site residues involved in interaction were LYS82, LYS85, SER89, TYR176, PHE170, PHE177. Four steroidal Lactone-based withanolide backbone of these compounds played a critical role in stabilizing their position in the active site pocket. 100 ns molecular dynamics simulation and subsequent trajectory analysis through structural deviation and compactness, principal components, free energy landscape and correlation matrix confirmed the stability of CST-2,3-Didehydrosomnifericin complex throughout the simulation and therefore is considered as the most potent drug candidate for CST inhibition and Withasomidienone as the second most potent drug candidate. The reverse pharmacophore analysis further confirmed the specificity of these two compounds towards CST as no major cross targets were identified. Thus, identified compounds in this study strongly present their candidature for oral drug and provide route for further development of more specific CST inhibitors. [ABSTRACT FROM AUTHOR]

We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study, we synthesized and tested radically altered IMT isomers (IMTi's) that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization. [ABSTRACT FROM AUTHOR]

As an AAA + ATPase, thyroid hormone receptor interacting protein 13 (TRIP13) primarily functions in DNA double-strand break repair, chromosome recombination, and cell cycle checkpoint regulation; aberrant expression of TRIP13 can result in chromosomal instability (CIN). According to recent research, TRIP13 is aberrantly expressed in a variety of cancers, and a patient's poor prognosis and tumor stage are strongly correlated with high expression of TRIP13. Tumor cell and subcutaneous xenograft growth can be markedly inhibited by TRIP13 knockdown or TRIP13 inhibitor administration. In the initiation and advancement of human malignancies, TRIP13 seems to function as an oncogene. Based on available data, TRIP13 may function as a biological target and biomarker for cancer. The creation of inhibitors that specifically target TRIP13 may present novel approaches to treating cancer. [ABSTRACT FROM AUTHOR]

Poly(ADP‐ribose) polymerase‐10 (PARP10) is a critical enzyme involved in DNA damage repair. Its function in cellular repair mechanisms has been implicated in the development of chemoresistance and radioresistance in cancer cells. Consequently, PARP10 inhibition represents a promising, albeit challenging, and therapeutic target for various cancer types. This study aims to discover new PARP10 potential inhibitors via a hybrid of in silico approaches. Initially, pharmacophore‐based virtual screening was conducted on the ZINC and NCI databases. The resulting compounds were subsequently subjected to molecular docking studies to identify potential new PARP10 inhibitors. Subsequently, classical molecular dynamics (MD) simulations were conducted to evaluate and compare the dynamic behavior of the selected ligand, veliparib, and OUL35, a selective PARP10 inhibitor. Ultimately, compound ZINC20906412 was found as a potential lead compound based on its docking score and favorable interactions within the PARP10 active site. This compound may offer therapeutic potential for cancer treatment. [ABSTRACT FROM AUTHOR]

The search and development of effective sirtuin small molecule inhibitors (SIRTIs) continues to draw great attention due to their wide range of pharmacological applications. Based on SIRTs' involvement in different biological pathways, their ligands were investigated for many diseases, such as cancer, neurodegenerative disorders, diabetes, cardiovascular diseases and autoimmune diseases. The elucidation of a substantial number of SIRT2–ligand complexes is steering the identification of novel and more selective modulators. Among them, SIRT2 in the presence of the SirReal2 analog series was the most studied. On this basis, we recently reported structure-based analyses leading to the discovery of thiazole-based compounds acting as SIRT2 inhibitors (T1, SIRT2 IC50 = 17.3 µM). Herein, ligand-based approaches followed by molecular docking simulations allowed us to evaluate in silico a novel small series of thiazoles (3a–3d and 5a, 5d) as putative SIRT2 inhibitors. Results from the computational studies revealed comparable molecular interaction fields (MIFs) and docking positionings of most of these compounds with respect to reference SIRT2Is. Biochemical and biological assays validated this study and pointed to compound 5a (SIRT2 IC50 = 9.0 µM) as the most interesting SIRT2I that was worthy of further development as an anticancer agent. [ABSTRACT FROM AUTHOR]

The Rho GTPase signaling pathway is responsible for cell-specific processes, including actin cytoskeleton organization, cell motility, cell division, and the transcription of specific genes. The implications of RhoA and the downstream effector ROCK2 in cancer epithelial-mesenchymal transition, migration, invasion, and therapy resistance associated with stem cells highlight the potential of targeting RhoA/ROCK2 signaling in therapy. Tumor relapse can occur due to cancer cells that do not fully respond to adjuvant chemoradiotherapy, targeted therapy, or immunotherapy. Rho signaling-mediated mitotic defects and cytokinesis failure lead to asymmetric cell division, allowing cells to form polyploids to escape cytotoxicity and promote tumor recurrence and metastasis. In this review, we elucidate the significance of RhoA/ROCK2 in the mechanisms of cancer progression and summarize their inhibitors that may improve treatment strategies. [ABSTRACT FROM AUTHOR]

Deubiquitinating enzymes (DUBs) prevent ubiquitination by eliminating ubiquitin from their substrates. Deubiquitinating enzymes have important roles in a number of cell biology subfields that are highly relevant to diseases like neurodegeneration, cancer, autoimmune disorders, and long-term inflammation. Deubiquitinating enzymes feature a well-defined active site and, for the most part, catalytic cysteine, which makes them appealing targets for small-molecule drug development. Ubiquitin-specific protease 46 (USP46) is a member of the ubiquitin-specific protease family, the largest subfamily of DUBs. Over the past 10 years, some studies have steadily demonstrated the significance of USP46 in several biological processes, although it was identified later and early research progress was modest. Specifically, in the last few years, the carcinogenic properties of USP46 have become more apparent. In the current review, we provide a comprehensive overview of the current knowledge about USP46 including its characteristics, structure, inhibitors, function in diseases, especially in the nervous system, and the correlation of USP46 with cancers. [ABSTRACT FROM AUTHOR]

PDIA3 is a pleiotropic protein primarily located in the endoplasmic reticulum where it is involved in protein folding, catalyzing the formation, breakage, and rearrangement of disulfide bonds. PDIA3 is implicated in numerous pathologies such as cancer, inflammation, and neurodegeneration. Although punicalagin has been proven to be a highly promising PDIA3 inhibitor and can be used as target protein in glioblastoma, it does not have sufficient selectivity for PDIA3 and is a quite-large molecule. With the aim of finding punicalagin derivatives with a simplified structure, we selected punicalin, which lacks the hexahydroxy-diphenic acid moiety. Previous docking studies suggest that this part of the molecule is not involved in the binding with PDIA3. In this study we compared the ability of punicalin to bind and inhibit PDIA3 and PDIA1. Tryptophan fluorescence quenching and disulfide reductase activity (using both glutathione and insulin as substrates) were evaluated, demonstrating the ability of punicalin to bind and inhibit PDIA3 even to a lesser extent compared to punicalagin. On the other hand, punicalin showed a very low inhibition activity towards PDIA1, demonstrating a higher selectivity for PDIA3. Protein thermal shift assay evidenced that both proteins can be destabilized by punicalin as well as punicalagin, with PDIA3 much more sensitive. Additionally, punicalin showed a higher change in the thermal stability of PDIA3, with a shift up to 8 °C. This result could explain the presence of PDIA3 aggregates, evidenced by immunofluorescence analysis, that accumulate within treated cells and that are more evident in the presence of punicalin. The results here obtained show punicalin is able to bind both proteins but with a higher selectivity for PDIA3, suggesting the possibility of developing new molecules with a simplified structure that are still able to selectively bind and inhibit PDIA3. [ABSTRACT FROM AUTHOR]

ABSTRACT Sickle cell disease (SCD) is a hereditary disorder characterized by vaso‐occlusion, inflammation, and tissue damage. Intercellular adhesion molecule 1 (ICAM‐1) plays a crucial role in the pathophysiology of SCD by promoting the adhesion of sickle cells to the endothelium, contributing to vaso‐occlusion and tissue damage. The ICAM‐1 gene encodes a glycoprotein that interacts with lymphocyte function–associated antigen 1 (LFA‐1) and macrophage 1‐antigen (Mac‐1) receptors, perpetuating inflammation, and oxidative stress. The NF‐κB signaling pathway regulates ICAM‐1 expression, which is elevated in patients with SCD, leading to increased endothelial cell activation and damage. Targeting ICAM‐1 and its interactions with sickle cells and the endothelium has emerged as a potential therapeutic strategy for managing SCD. This review highlights the complex interplay between ICAM‐1, sickle cells, and the endothelium, and discusses the potential of ICAM‐1‐targeted therapies for mitigating VOC and improving the quality of life for patients with SCD. [ABSTRACT FROM AUTHOR]

SUMMARY: Structural prediction by artificial intelligence can be powerful new instruments to discover novel protein–protein interactions, but the community still grapples with the implementation, opportunities and limitations. Here, we discuss and re‐analyse our in silico screen for novel pathogen‐secreted inhibitors of immune hydrolases to illustrate the power and limitations of structural predictions. We discuss strategies of curating sequences, including controls, and reusing sequence alignments and highlight important limitations caused by different platforms, sequence depth and computing times. We hope these experiences will support similar interactomic screens by the research community. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3α or GSK-3β often provides cytoprotective effects under such clinical conditions. However, available synthetic small molecule inhibitors are relatively non-specific, and their chronic use may lead to adverse effects. Therefore, screening for natural compound inhibitors to identify the isoform-specific inhibitors may provide improved clinical utility. Here, we screened 70 natural compounds to identify novel natural GSK-3 inhibitors employing comprehensive in silico and biochemical approaches. Molecular docking and pharmacokinetics analysis identified two natural compounds Psoralidin and Rosmarinic acid as potential GSK-3 inhibitors. Specifically, Psoralidin and Rosmarinic acid exhibited the highest binding affinities for GSK-3α and GSK-3β, respectively. Consistent with in silico findings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3α (IC50 = 2.26 μM) vs. GSK-3β (IC50 = 4.23 μM) while Rosmarinic acid was found to be more potent against GSK-3β (IC50 = 2.24 μM) than GSK-3α (IC50 = 5.14 μM). Taken together, these studies show that the identified natural compounds may serve as GSK-3 inhibitors with Psoralidin serving as a better inhibitor for GSK-3α and Rosmarinic for GSK-3β isoform, respectively. Further characterization employing in vitro and preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers. Schematic diagram shows the molecular docking to simulate how natural compounds might bind to the crystal structure of GSK-3 enzymes. This was followed by additional in silico analyses, including assessments of druglikeness, potential toxicity, bioactivity scores, and pharmacokinetic properties. Through this multi-step screening process, Psoralidin and Rosmarinic acid emerged as potential inhibitors of GSK-3α and GSK-3β isoforms, respectively. Finally, based on their predicted high binding energy with both GSK-3α and GSK-3β, Psoralidin and Rosmarinic acid were selected for further testing using a kinase assay. This assay confirmed their inhibitory potential, demonstrating higher potency against GSK-3α and GSK-3β, respectively. [Display omitted] • Current GSK-3 inhibitors lack specificity and cause side effects. • This study identifies potential GSK-3 isoform-specific natural compounds. • Psoralidin is likely a better inhibitor for GSK-3α while Rosmarinic for GSK-3β. • These natural compounds may be promising future treatments. [ABSTRACT FROM AUTHOR]

The corrosion inhibition effects of Drimia maritima (L.) Stearn sin. Urginea maritima (L.) Backer on three different materials, i.e., as-cast Al-7 wt.% Si alloy, SAE 1020 low carbon steel, and commercially pure Al samples, into a stagnant and naturally aerated 0.5 M NaCl solution are evaluated. For this purpose, both the potentiodynamic polarization curves and electrochemical impedance spectroscopy with an equivalent circuit are utilized. It is found that inhibition effect increases up to certain minor Drimia maritima content. Adsorption isotherms (e.g., Langmuir and Temkin) indicate that all three examined materials comprise physical adsorption mechanisms. Al-Si alloys attained inhibition efficiencies of about 96% at 25 °C with 1250 ppm of Drimia maritima and ~43% with 625 ppm at 45 °C. On the other hand, the cp. Al and SAE 1020 samples attain ~89% and 68% with 1250 ppm and 500 ppm at 25 °C, respectively. This clearly indicates that the dosage of Drimia maritima green inhibitor into NaCl solution possesses certain susceptibility for each distinctive material examined. Impedance parameters obtained by using CNLS (complex non-linear least squares simulations) are correlated and discussed. [ABSTRACT FROM AUTHOR]

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A series of N-alkylfuran-2-carboxamide derivatives was easily prepared through direct acylation of diverse amines with 2-furoyl chloride. Using an E. coli reporter strain, all compounds were then examined as LuxR-regulated quorum sensing modulators for their agonistic or antagonistic activity. Compounds with a C8 or specially C6 alkyl chain with a comparable chain length with the natural ligand of LuxR were found to be antagonists with an IC50 value of 25 µM. Competition experiments between the N-hexylfuran-2-carboxamide with the natural ligand indicate that the LuxR activity could be restored with high concentration of LuxR ligand. Conformational analysis, docking simulations and protein-ligand affinity prediction suggest that furan-2-carboxamide derivatives interact within the LuxR binding site via H-bonds of the C = O oxygen atom with Tyr62 OH and of the amide NH with Asp79 carboxylate, Tyr62 and Asp79 being two important conserved residues in the LuxR family. The binding mode also suggests that the absence of the hydrogen bond with Trp66, normally observed for the amide retroisoster analogs having the lactone instead of the furyl moiety, is not deleterious to the ability to interact and induce inhibition. [ABSTRACT FROM AUTHOR]

Mycobacterial membrane protein Large 3 (MmpL3) of Mycobacterium tuberculosis (Mtb) is crucial for the translocation of trehalose monomycolate (TMM) across the inner bacterial cell membrane, making it a promising target for anti‐tuberculosis (TB) drug development. While several structural, microbiological, and in vitro studies have provided significant insights, the precise mechanisms underlying TMM transport by MmpL3 and its inhibition remain incompletely understood at the atomic level. In this study, molecular dynamic (MD) simulations for the apo form and seven inhibitor‐bound forms of Mtb MmpL3 were carried out to obtain a thorough comprehension of the protein's dynamics and function. MD simulations revealed that the seven inhibitors in this work stably bind to the central channel of the transmembrane domain and primarily forming hydrogen bonds with ASP251, ASP640, or both residues. Through dynamical cross‐correlation matrix and principal component analysis analyses, several types of coupled motions between different domains were observed in the apo state, and distinct conformational states were identified using Markov state model analysis. These coupled motions and varied conformational states likely contribute to the transport of TMM. However, simulations of inhibitor‐bound MmpL3 showed an enlargement of the proton channel, potentially disrupting coupled motions. This indicates that inhibitors may impair MmpL3's transport function by directly blocking the proton channel, thereby hindering coordinated domain movements and indirectly affecting TMM translocation. [ABSTRACT FROM AUTHOR]

Many pathogenic bacteria form biofilms that are resistant to not only host immune defenses but also antibiotics, posing a need for the development of strategies to control biofilms. In this study, to prevent biofilm formation of the fulminating foodborne pathogen Vibrio vulnificus, chemical libraries were extensively screened to identify a small molecule inhibiting the activity of BrpR, a transcriptional regulator for biofilm genes. Accordingly, the BrpR inhibitor BFstatin [N1-(2-chloro-5-fluorophenyl)-N3-propylmalonamide], with a half-maximal effective concentration of 8.01 µM, was identified. BFstatin did not interfere with bacterial growth or exhibit cytotoxicity to the human epithelial cell line. BFstatin directly bound to BrpR and interrupted its binding to the target promoter DNAs of the downstream genes. Molecular dynamics simulation of the interaction between BFstatin and BrpR proposed that BFstatin modifies the structure of BrpR, especially the DNA-binding domain. Transcriptomic analyses revealed that BFstatin reduces the expression of the BrpR regulon including the cabABC operon and brp locus which contribute to the production of biofilm matrix of V. vulnificus. Accordingly, BFstatin diminished the biofilm levels of V. vulnificus by inhibiting the matrix development in a concentration-dependent manner. Altogether, BFstatin could be an anti-biofilm agent targeting BrpR, thereby rendering V. vulnificus more susceptible to host immune defenses and antibiotics. [ABSTRACT FROM AUTHOR]

The Caf1/CNOT7 nuclease is a catalytic component of the Ccr4-Not deadenylase complex, which is a key regulator of post-transcriptional gene regulation. In addition to providing catalytic activity, Caf1/CNOT7 and its paralogue Caf1/CNOT8 also contribute a structural function by mediating interactions between the large, non-catalytic subunit CNOT1, which forms the backbone of the Ccr4-Not complex and the second nuclease subunit Ccr4 (CNOT6/CNOT6L). To facilitate investigations into the role of Caf1/CNOT7 in gene regulation, we aimed to discover and develop non-nucleoside inhibitors of the enzyme. Here, we disclose that the tri-substituted 2-pyridone compound 5-(5-bromo-2-hydroxy-benzoyl)-1-(4-chloro-2-methoxy-5-methyl-phenyl)-2-oxo-pyridine-3-carbonitrile is an inhibitor of the Caf1/CNOT7 nuclease. Using a fluorescence-based nuclease assay, the activity of 16 structural analogues was determined, which predominantly explored substituents on the 1-phenyl group. While no compound with higher potency was identified among this set of structural analogues, the lowest potency was observed with the analogue lacking substituents on the 1-phenyl group. This indicates that substituents on the 1-phenyl group contribute significantly to binding. To identify possible binding modes of the inhibitors, molecular docking was carried out. This analysis suggested that the binding modes of the five most potent inhibitors may display similar conformations upon binding active site residues. Possible interactions include π-π interactions with His225, hydrogen bonding with the backbone of Phe43 and Van der Waals interactions with His225, Leu209, Leu112 and Leu115. [ABSTRACT FROM AUTHOR]

This study proposes a novel therapeutic strategy for cancer management by combining the antitumor effects of hydrogen sulfide (H2S) and inhibition of carbonic anhydrases (CAs; EC 4.2.1.1), specifically isoforms IV, IX, and XII. H2S has demonstrated cytotoxicity against various cancers at high concentrations. The inhibition of tumor-associated CAs leads to lethal intracellular alkalinization and acidification of the extracellular tumor microenvironment and restores tumor responsiveness to the immune system, chemotherapy, and radiotherapy. The study proposes H2S donor–CA inhibitor (CAI) hybrids for tumor management. These compounds effectively inhibit the target CAs, release H2S consistently, and exhibit potent antitumor effects against MDA-MB-231, HCT-116, and A549 cancer cell lines. Notably, some compounds display high cytotoxicity across all investigated cell lines. Derivative 30 shows a 2-fold increase in cytotoxicity (0.93 ± 0.02 µM) under chemically induced hypoxia in HCT-116 cells. These compounds also disturb the cell cycle, leading to a reduction in cell populations in G0/G1 and S phases, with a notable increase in G2/M and Sub-G1. This disruption is correlated with induced apoptosis, with fold increases of 37.2, 24.5, and 32.9 against HCT-116 cells and 14.2, 13.1, and 19.9 against A549 cells compared to untreated cells. These findings suggest the potential of H2S releaser–CAI hybrids as effective and versatile tools in cancer treatment. [ABSTRACT FROM AUTHOR]

While previous studies have suggested that biochar, nitrification inhibitors, and urease inhibitors may reduce soil greenhouse gas emissions, their effectiveness in soils irrigated with alternative water resources remains unclear. To compensate for this, reclaimed water and livestock wastewater were utilized as alternative water resources alongside groundwater control. Nitrapyrin and N-(n-butyl) thiophosphoric triamide and biochar were applied to the soil either individually or in combination, and a no-substance treatment (NS) was included for comparison. The results revealed that reclaimed water and livestock wastewater irrigation exacerbated the global warming potential. Compared to the NS, all exogenous substance treatments suppressed nitrous oxide (N2O) emissions while increasing carbon dioxide (CO2) emissions, and affecting methane (CH4) emissions varied across treatments irrespective of the water types. Interestingly, the additional biochar reduced the inhibitory effect of the inhibitors on the greenhouse effect. Using nitrification inhibitors reduced the global warming potential by 48.3% and 50.1% under reclaimed water and livestock wastewater irrigation, respectively. However, when nitrification inhibitors were applied in combination with biochar, the global warming potential was increased by 52.1–83.4% compared to nitrification inhibitors alone, and a similar trend was also observed in the scenario of urease inhibitors, with increases ranging from 8.8 to 35.1%. Therefore, the combined application of biochar and inhibitors should be approached cautiously, considering the potential for increased greenhouse gas emissions. [ABSTRACT FROM AUTHOR]

Methyltransferase-like protein is a ubiquitous enzyme-like protein in the human body, with binding domains for nucleic acids, proteins and other small molecules, and plays an important role in a variety of biological behaviours in normal organisms and diseases, characterised by the presence of a methyltransferase-like structural domain and a structurally conserved SAM-binding domain formed by the seven-stranded β-fold structure in the center of the protein. With the deepening of research, the METTL protein family has been found to be abnormally expressed in a variety of tumor diseases, and the clarification of its relationship with tumor diseases can be used as a molecular therapeutic target and has an important role in the prognosis of tumors. In this paper, we review the structure, biological process, immunotherapy, drug-targeted therapy, and markers of the METTL protein family to provide new ideas for the diagnosis and treatment of tumors. [ABSTRACT FROM AUTHOR]

Naturally occurring gas hydrates are established as an abundant reserve of natural gas. Production initiatives raised challenges such as low production rate, freezing problems, water, and sand production along with geomechanical concerns. Recent studies suggest that fracturing the sediment can significantly improve the conductivity and productivity of such reserves. This study is an initiative to verify the suitability of conventionally used polymer (guar) for fracturing at extremely low temperatures along with the integration of widely available gas hydrate inhibitors for efficient stimulation. Established inhibitors such as NaCl, CaCl 2 and KCl were introduced to linear and crosslinked gels to study their compatibility with the reference guar-based gels. The inhibitor integrated linear gel samples demonstrated similar performance trends to that of the reference gel establishing their compatibility with the polymer, whereas the inhibitor integrated crosslinked samples displayed deswelling nature. The low concentration inhibitor integrated linear gel samples performed superior to the reference gel whereas the high concentration sample inhibited the swelling performance of the polymer. Both the reference and inhibitor integrated linear gel samples gradually disintegrated after 48 h leaving behind soft cloudy residue, whereas the inhibitor integrated crosslinked samples rapidly released water and contracted into a solid residue which can cause serious flow related disruptions during operations and apparently damage the conductivity of the sediment for long term. This study delivers crucial understanding on how various salts interact with guar polymers at low temperatures and whether their presence can be a boon or bane during the design of a fracturing fluid. • Low temperature fracturing of hydrate-bearing sediments for improved gas recovery. • Integration of hydrate inhibitors with conventional gelling polymer used in hydraulic fracturing. • Inhibitor integrated linear gel samples demonstrated good integrity during tests. • Inhibitor integrated low concentration samples performed superiorly. • Inhibitor integrated crosslinked gels prone to deswelling and residue formation. [ABSTRACT FROM AUTHOR]

The protein tyrosine phosphatase 1B (PTP1B) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). Many PTP1B inhibitors have been reported, however, most of them lack high specificity and have adverse effects. Designing effective PTP1B inhibitors requires understanding the molecular mechanism of action between inhibitors and PTP1B. To this end, molecular dynamics (MD) simulations and molecular mechanics Poisson Boltzmann Surface Area (MM-PB/ SA) methods were used to observe the binding patterns of compounds with similar pentacyclic triterpene parent ring structures but different inhibition abilities. Through structure and energy analysis, we found that the positions of cavities and substituents significantly affect combining capacity. Besides, we constructed a series of potential inhibitor molecules using LUDI and rational drug design methods. The ADMET module of Discovery Studio 2020 was used to predict the properties of these inhibitor molecules. Lastly, we obtained compounds with low toxicity and significant inhibitory activity. The study will contribute to the treatment of T2DM. [ABSTRACT FROM AUTHOR]

This article, published in Frontiers in Pharmacology, explores the design of novel inhibitors for ischemia/reperfusion injury targeting ferroptosis. Ischemic cardiovascular disease, a leading cause of death worldwide, is caused by reduced blood flow to the heart. The article emphasizes the importance of understanding the mechanisms of cardiovascular disease progression and the role of ferroptosis in ischemic cardiovascular disease. It presents research on the use of novel inhibitors, such as pyrroloquinoline quinone (PQQ) and activating transcription factor 3 (ATF3), in protecting the heart from ischemia/reperfusion injury by inhibiting ferroptosis. The article discusses the potential therapeutic use of ferroptosis inhibitors for various cardiovascular diseases and highlights three specific studies that investigate the role of different compounds in inhibiting ferroptosis and improving cardiac health. These studies focus on Resveratrol, Allicin, and ATF3 expression inhibition as potential treatments for myocardial infarction and atherosclerosis. The article concludes that these studies provide valuable insights into the mechanisms of ferroptosis and offer new possibilities for clinical treatment. [Extracted from the article]

Poly(ADP-ribose) polymerase (PARP) inhibitors have been proposed as pharmacological agents in the treatment of various diseases. Recently, factors and mechanisms responsible for regulating PARP catalytic activity have been identified, some of which can significantly influence the effectiveness of inhibitors of this enzyme. In this regard, it is important to develop new models and methods that would reflect the cellular context in which PARP functions. We proposed to use digitonin-permeabilized adherent cells to study poly(ADP-ribosyl)ation reaction (PARylation) in order to maintain the nuclear localization of PARP and to control the concentrations of its substrate (NAD+) and tested compounds in the cell. A specific feature of the approach is that before permeabilization, cellular PARP is converted to the DNA-bound state under conditions preventing premature initiation of the PARylation reaction. Experiments were carried out in rat H9c2 cardiomyoblasts. The activity of PARP in permeabilized cells was analyzed by measuring the immunofluorescence of the reaction product poly(ADP-ribose). The method was verified in the studies of PARP inhibition by the classic inhibitor 3-aminobenzamide and a number of new 7-methylguanine derivatives. One of them, 7,8-dimethylguanine, was found to be a stronger inhibitor compared to 7-methylguanine, due to a formation of additional hydrophobic contact with the protein. The proposed approach opens up new prospects for studying the mechanisms of PARP activity regulation in cells and can be used in high-throughput screening of PARP inhibitors. [ABSTRACT FROM AUTHOR]

This study evaluates the effectiveness of KMnO4, MK3 and 1-butanol inhibitors on corrosion of AISI 314 and AISI 304 stainless steels using linear and potentiodynamic polarization in 0.1 M HNO3. The metrics like corrosion potential (Ecorr), current density (jcorr) and polarization resistance (Rp) influence the inhibitor efficacy. The inhibitors improved electrochemical parameters significantly, indicating strong anti-corrosive properties. 1-Butanol had the strongest effect, enhancing corrosion potential and drastically reducing corrosion current density, demonstrating superior protection. The results indicated that without inhibitors, both steels showed higher corrosion rates and more negative potentials, reflecting their susceptibility to corrosion. The introduction of inhibitors markedly improved these parameters, particularly with 1-butanol, which significantly enhanced the polarization resistance and shifted the corrosion potential towards less negative values. The potentiodynamic results highlighted the dynamic effectiveness of inhibitors, reinforcing their role in mitigating corrosion under varied conditions. The study underscores the importance of selecting the appropriate inhibitors to enhance the durability and longevity of stainless steels in acidic environments, with 1-butanol showing the potential for industrial applications requiring high corrosion resistance. This necessitates comprehensive testing to accurately measure inhibitor capabilities in different conditions. [ABSTRACT FROM AUTHOR]

Botulinum neurotoxins (BoNT) inhibit neuroexocytosis, leading to the potentially lethal disease botulism. BoNT serotype A is responsible for most human botulism cases, and there are no approved therapeutics to treat already intoxicated patients. A growing body of research has demonstrated that BoNT/A can escape into the central nervous system, and therefore, identification of BoNT/A inhibitors that can penetrate BBB and neutralize the toxin within intoxicated neurons would be important. We previously identified an FDA‐approved, orally bioavailable compound, KX2‐391 (Tirbanibulin) that inhibits BoNT/A in motor neuron assays. Recently, a structural analog of KX2‐391, KX2‐361, has been shown to exhibit good oral bioavailability and cross BBB with high efficiency in mouse experiments. Therefore, in this work, we evaluated the inhibitory effects of KX2‐361 against BoNT/A. Toward this goal, we first evaluated the compound for its effects on cell viability in PC12 cells, via MTT assay, and in mouse embryonic stem cell (mESC)‐derived motor neurons, with imaging‐based assays. Following, we tested KX2‐361 in mESC‐derived motor neurons intoxicated with BoNT/A holotoxin, and the compound exhibited activity against the toxin in both pre‐ and post‐intoxication conditions. Excitingly, KX2‐361 also inhibited BoNT/A enzymatic component (light chain; LC) in PC12 cells transfected with BoNT/A LC. Furthermore, our molecular docking analyses suggested that KX2‐361 can directly bind to BoNT/A LC. Medicinal chemistry approaches to develop structural analogs of KX2‐361 to increase its efficacy against BoNT/A may provide a critical lead compound with BBB penetration capacity for drug development efforts against BoNT/A intoxication. [ABSTRACT FROM AUTHOR]

Simple Summary: This review focuses on the current advancements in the development of inhibitors and the application of kinesin family member 20A (KIF20A) as a cancer immunotherapy target. KIF20A, a mitotic kinesin overexpressed in various cancers, plays a pivotal role in cell division and is increasingly recognized as a crucial factor in tumor progression and a potential target for novel cancer treatments. The analysis begins with a detailed examination of the gene expression and protein structure of KIF20A, highlighting its interaction with critical cellular components that influence key processes such as Golgi membrane transport and mitotic spindle assembly. The primary focus is on the development of specific KIF20A inhibitors, detailing their roles and the challenges encountered in enhancing their efficacy, such as achieving specificity, overcoming tumor resistance, and optimizing delivery systems. Additionally, it delves into the prognostic value of KIF20A across multiple cancer types, emphasizing its role as a novel tumor-associated antigen, which lays the groundwork for the development of targeted peptide vaccines. The therapeutic efficacy of these vaccines as demonstrated in recent clinical trials is discussed. Future directions are proposed, including the integration of precision medicine strategies to personalize treatments and the use of combination therapies to improve outcomes. By concentrating on the significant potential of KIF20A as both a direct target for inhibitors and an antigen in cancer vaccines, this review sets a foundation for future research aimed at harnessing KIF20A for effective cancer treatment. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen accountable for severe illness and mortality among immunocompromised individuals due to its extraordinary resistance to antibiotics. The regulation of pathogenic traits in P. aeruginosa is governed by a quorum sensing (QS) signaling molecule named acyl homoserine lactone (AHL). The present study investigated the inhibitory effects of the compound, Artocarpus heterophyllus Lam (A. heterophyllus), on the number of AHL-dependent components produced by P. aeruginosa (PAO1). A. heterophyllus is considered as a beneficial natural compound with notable inhibitory effects on several pathogens. The present study investigated the antimicrobial and antibiofilm activities of A. heterophyllus against PAO1 through in vitro experiments, including minimum inhibitory concentration tests, biofilm inhibition assays and growth curve analysis. The results demonstrated that the methanolic extract of A. heterophyllus at a concentration of 10 mg/ml effectively inhibited PAO1. Additionally, the extract exhibited a 55.12% biofilm inhibitory effect at the lowest sub-inhibitory concentration of 2.5 mg/ml, without affecting planktonic cell growth. On the whole, the findings of the present study indicate the prospective signifi- cance of A. heterophyllus as an anti-pathogenic agent, which is effective in reducing QS-dependent infection in PAO1. [ABSTRACT FROM AUTHOR]

The interaction of the tax system with business entities was an area of academic research for Professor C John Taylor, especially the tax treatment of companies and trusts, and the influence of the tax impost on these. This article reports a study of 48 advisors in the small and medium enterprise (SME) sector and explores the factors that may inhibit SMEs from structuring, as well as the techniques used to reduce these inhibitors. The results demonstrate that advisors perceive transfer costs of capital gains tax and stamp duty as major inhibitors, but they are able to use mechanisms to reduce them. [ABSTRACT FROM AUTHOR]

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Thin layer chromatography bioautographic assays facilitate the acquisition of activity-profile chromatograms and assist in pinpointing active constituents within complex mixtures by observing the inhibition halos they produce. Peroxidase is an enzyme implicated in the browning of different fresh cut vegetables and in several diseases. A peroxidase bioautographic assay was developed, based on enzyme agarose immobilization and the 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt/radical cation (ABTS/ABTS·+) reporter system. Peroxidase was purified from potatoes with the aim to detect specific inhibitors. To reduce false positives, a non-enzymatic assay was also employed. The best results are obtained when a solution containing agarose, ABTS, hydrogen peroxide, and peroxidase in phosphate buffer is poured over the TLC plate (final concentrations: 0.031 mmoles/cm2, 0.239 µmoles/cm2, and 84.04 U/cm2) and incubated for 70 min. Limit of detection and quantification for quercetin is 0.16 µg and 0.54 µg, respectively. The developed system is able to detect quercetin in a Solidago chilensis Meyen extract and a peroxidase inhibitor in a Cichorium intybus L. extract. Therefore, the assay can detect inhibitory constituents in complex mixtures and differentiate between peroxidase inhibitors and ABTS·+ radical scavengers before any preparative fractionation, helping to take early operational decisions that can save time and resources. [ABSTRACT FROM AUTHOR]

Background: Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1) is a central regulator of programmed axon death and a crucial nicotinamide adenine dinucleotide (NAD+) hydrolase (NADase) in mammalian tissues, hydrolyzing NAD+ and playing an important role in cellular NAD+ recycling. Abnormal SARM1 expression is linked to axon degeneration, which causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Methods: In this study, we use PC6 assay of hydrolase activity, DRG axon regeneration and CIPN model to screen for potent SARM1 Inhibitors. Results: Two novel SARM1 inhibitors (compound 174 and 331P1) are charcterized for its high potency for SARM1 NADase. In a chemotherapy-induced peripheral neuropathy (CIPN) myopathy model, compound 331P1 treatment prevented the decline in neurofilament light chain (NfL) levels caused by axonal injury in a dose-dependent manner, associated with elevated intraepidermal nerve fiber (IENF) intensity in mouse foot paw tissue, suggesting its functionality in reversing axon degeneration. Conclusions: The newly designed SARM1 inhibitor 331P1 is a promising candidate due to its excellent in vivo efficacy, favorable CYP inhibition properties, and attractive safety profiles. The 331P1 compound possesses the potential to be developed as a novel neuroprotective therapy that can prevent or halt the neurodegenerative process in CIPN. [ABSTRACT FROM AUTHOR]

Insulin‐regulated aminopeptidase (IRAP) is an enzyme with important biological functions and the target of drug‐discovery efforts. We combined in silico screening with a medicinal chemistry optimization campaign to discover a nanomolar inhibitor of IRAP based on a pyrazolylpyrimidine scaffold. This compound displays an excellent selectivity profile versus homologous aminopeptidases, and kinetic analysis suggests it utilizes an uncompetitive mechanism of action when inhibiting the cleavage of a typical dipeptidic substrate. Surprisingly, the compound is a poor inhibitor of the processing of the physiological cyclic peptide substrate oxytocin and a 10mer antigenic epitope precursor but displays a biphasic inhibition profile for the trimming of a 9mer antigenic peptide. While the compound reduces IRAP‐dependent cross‐presentation of an 8mer epitope in a cellular assay, it fails to block in vitro trimming of select epitope precursors. To gain insight into the mechanism and basis of this unusual selectivity for this inhibitor, we solved the crystal structure of its complex with IRAP. The structure indicated direct zinc(II) engagement by the pyrazolylpyrimidine scaffold and revealed that the compound binds to an open conformation of the enzyme in a pose that should block the conformational transition to the enzymatically active closed conformation previously observed for other low‐molecular‐weight inhibitors. This compound constitutes the first IRAP inhibitor targeting the active site that utilizes a conformation‐specific mechanism of action, provides insight into the intricacies of the IRAP catalytic cycle, and highlights a novel approach to regulating IRAP activity by blocking its conformational rearrangements. [ABSTRACT FROM AUTHOR]

The assessment of two diamine derivatives, TMD and IPDA, as corrosion inhibitors for aluminium in hydrochloric acid (HCl) at concentrations of 0.2 M, 0.3 M, and 0.4 M. (4S)—2,2,4-trimethyl hexane-1,6-diamine (TMD) and (1R,3R)-3-(amino methyl)-3,5,5-trimethyl cyclohexane-1-amine (IPDA) are verified for their ability to inhibit corrosion of Al in acidic conditions. The evaluation is conducted using electrochemical impedance spectroscopy (EIS), potentiodynamics polarization (PDP), and gravimetric methods. The inhibitors' effectiveness depends on their concentration (ranging from 20 to 50 mM) and molecular structure. Because TMD has more anchoring functional groups, it had the best inhibitory efficacy, reaching a maximum of 98.3% at 50 mM concentration. It is looked into how temperature (313–333 K) affects corrosion behaviour. As per Langmuir's adsorption isotherm, the temperature probably influences the ability of inhibitors to adsorb on the surface of aluminium, pointing to a monolayer adsorption mechanism. Calculated and described are the thermodynamics activation factors for the dissolution process of Al in both inhibited along uninhibited solutions. The stability of the inhibitor-Al contact and the reaction kinetics are revealed by these characteristics. The creation of a protective covering on the Al surfaces was validated by surface investigation techniques such as atomic force microscopy, scanning electron microscopy, and energy-dispersive X-ray (EDX) analysis, demonstrating the inhibitors' efficacy in preventing corrosion. The inhibitors' molecular chemical makeup as well as the degree of inhibitory efficacy is correlated in theoretical investigations employing molecular dynamics simulations and density functional theory. Theoretical calculations shed additional light on the adsorption mechanism. [ABSTRACT FROM AUTHOR]

Abstract Cerebroside sulfotransferase (CST) is considered as therapeutic target for substrate reduction therapy (SRT) for metachromatic leukodystrophy (MLD). The present study evaluates the therapeutic potential of 57 phytoconstituents of Withania somnifera against CST. Using binding score cutoff ≤-7.0 kcal/mol, top 10 compounds were screened and after ADME and toxicity-based screening, Withasomidienone, 2,4-methylene-cholesterol, and 2,3-Didehydrosomnifericin were identified as safe and potent drug candidates for CST inhibition. Key substrate binding site residues involved in interaction were LYS82, LYS85, SER89, TYR176, PHE170, PHE177. Four steroidal Lactone-based withanolide backbone of these compounds played a critical role in stabilizing their position in the active site pocket. 100 ns molecular dynamics simulation and subsequent trajectory analysis through structural deviation and compactness, principal components, free energy landscape and correlation matrix confirmed the stability of CST-2,3-Didehydrosomnifericin complex throughout the simulation and therefore is considered as the most potent drug candidate for CST inhibition and Withasomidienone as the second most potent drug candidate. The reverse pharmacophore analysis further confirmed the specificity of these two compounds towards CST as no major cross targets were identified. Thus, identified compounds in this study strongly present their candidature for oral drug and provide route for further development of more specific CST inhibitors.

Abstract The Rho GTPase signaling pathway is responsible for cell-specific processes, including actin cytoskeleton organization, cell motility, cell division, and the transcription of specific genes. The implications of RhoA and the downstream effector ROCK2 in cancer epithelial-mesenchymal transition, migration, invasion, and therapy resistance associated with stem cells highlight the potential of targeting RhoA/ROCK2 signaling in therapy. Tumor relapse can occur due to cancer cells that do not fully respond to adjuvant chemoradiotherapy, targeted therapy, or immunotherapy. Rho signaling-mediated mitotic defects and cytokinesis failure lead to asymmetric cell division, allowing cells to form polyploids to escape cytotoxicity and promote tumor recurrence and metastasis. In this review, we elucidate the significance of RhoA/ROCK2 in the mechanisms of cancer progression and summarize their inhibitors that may improve treatment strategies.

Abstract Methyltransferase-like protein is a ubiquitous enzyme-like protein in the human body, with binding domains for nucleic acids, proteins and other small molecules, and plays an important role in a variety of biological behaviours in normal organisms and diseases, characterised by the presence of a methyltransferase-like structural domain and a structurally conserved SAM-binding domain formed by the seven-stranded β-fold structure in the center of the protein. With the deepening of research, the METTL protein family has been found to be abnormally expressed in a variety of tumor diseases, and the clarification of its relationship with tumor diseases can be used as a molecular therapeutic target and has an important role in the prognosis of tumors. In this paper, we review the structure, biological process, immunotherapy, drug-targeted therapy, and markers of the METTL protein family to provide new ideas for the diagnosis and treatment of tumors.

Alzheimer’s Disease (AD) is a multifaceted neurodegenerative disease predominantly defined by the extracellular accumulation of amyloid-β (Aβ) peptide. In light of this, in the past decade, several clinical approaches have been used aiming at developing peptides for therapeutic use in AD. The use of cationic arginine-rich peptides (CARPs) in targeting protein aggregations has been on the rise. Also, the process of peptide development employing computational approaches has attracted a lot of attention recently. Using a structure database containing pentapeptides made from 20 L-α amino acids, we employed molecular docking to sort pentapeptides that can bind to Aβ42, then performed molecular dynamics (MD) analyses, including analysis of the binding stability, interaction energy, and binding free energy to screen ligands. Transmission electron microscopy (TEM), circular dichroism (CD), thioflavin T (ThT) fluorescence detection of Aβ42 polymerization, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, and the flow cytometry of reactive oxygen species (ROS) were carried out to evaluate the influence of pentapeptides on the aggregation and cell toxicity of Aβ42. Two pentapeptides (TRRRR and ARRGR) were found to have strong effects on inhibiting the aggregation of Aβ42 and reducing the toxicity of Aβ42 secreted by SH-SY5Y cells, including cell death, reactive oxygen species (ROS) production, and apoptosis.

In this investigation, we explored the corrosion inhibition mechanism of an imidazoline quaternary ammonium salt (IQA) on J55 steel in simulated annulus environment through a series of experiments, including electrochemical testing, stress corrosion immersion experiments, and hydrogen permeation testing. Our findings reveal that IQA functions as a mixed-type inhibitor, exerting its inhibitory action through chemical adsorption. Notably, it exhibits a stronger inhibitory effect on the anodic dissolution reaction compared to the cathodic hydrogen evolution reaction. Despite the minor influence of tensile plastic strain on the average inhibition efficiency, it notably exacerbates pitting and initiates stress corrosion cracking. This underscores the limitation of average inhibition efficiency in accurately assessing IQA's efficacy against stress corrosion. Additionally, hydrogen permeation experiments and electrochemical testing demonstrate that plastic strain diminishes IQA's inhibitory effect on the cathodic hydrogen evolution reaction, facilitating hydrogen diffusion into the steel substrate and thereby exacerbating stress corrosion in J55 steel. Consequently, at low IQA inhibitor concentrations (as in this study, 12.5 mg L−1), despite high average inhibition efficiency, it proves ineffective in mitigating stress corrosion.

Proteomic studies have identified moesin (MSN), a protein containing a four-point-one, ezrin, radixin, moesin (FERM) domain, and the receptor CD44 as hub proteins found within a coexpression module strongly linked to Alzheimers disease (AD) traits and microglia. These proteins are more abundant in Alzheimers patient brains, and their levels are positively correlated with cognitive decline, amyloid plaque deposition, and neurofibrillary tangle burden. The MSN FERM domain interacts with the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) and the cytoplasmic tail of CD44. Inhibiting the MSN-CD44 interaction may help limit AD-associated neuronal damage. Here, we investigated the feasibility of developing inhibitors that target this protein-protein interaction. We have employed structural, mutational, and phage-display studies to examine how CD44 binds to the FERM domain of MSN. Interestingly, we have identified an allosteric site located close to the PIP2 binding pocket that influences CD44 binding. These findings suggest a mechanism in which PIP2 binding to the FERM domain stimulates CD44 binding through an allosteric effect, leading to the formation of a neighboring pocket capable of accommodating a receptor tail. Furthermore, high-throughput screening of a chemical library identified two compounds that disrupt the MSN-CD44 interaction. One compound series was further optimized for biochemical activity, specificity, and solubility. Our results suggest that the FERM domain holds potential as a drug development target. Small molecule preliminary leads generated from this study could serve as a foundation for additional medicinal chemistry efforts with the goal of controlling microglial activity in AD by modifying the MSN-CD44 interaction.