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Xanthine oxidase (XO), which plays a key role in purine metabolism, is an important target enzyme for the prevention and treatment of hyperuricemia. Inhibitory activity against XO is a common criterion for the screening of compounds with potential anti-hyperuricemic activity. In this study, 22 XO inhibitors were used to construct a 3D-QSAR pharmacophore model. Subsequently, molecular docking and in vitro activity evaluations were used to identify strong XO inhibitors from a list of 2000 natural compounds. The interaction mechanisms of these compounds with XO were analyzed based on inhibition kinetics and multi-spectral analyses. The pharmacophore model was composed of three hydrogen bond receptors and a hydrophobic center. The screened compounds - Diosmetin, Fisetin, and Genistein - all showed good XO inhibitory activity, with IC 50 values of 1.86 ± 0.11 μM, 5.83 ± 0.08 μM, and 7.56 ± 0.10 μM, respectively. Kinetic analysis, fluorescence quenching assays, and molecular docking experiments showed that Diosmetin, Fisetin, and Genistein docked near the same active site of XO, mainly affecting the microenvironment of tryptophan residues. These molecules showed static binding to XO via hydrogen bonds, hydrophobic interactions, and van der Waals forces. Diosmetin and Genistein were competitive inhibitors, whereas Fisetin was a mixed inhibitor. Infrared spectroscopy showed that Diosmetin, Fisetin, and Genistein increased the α-helix content of XO from 7.4 % to 16.6 %, 21.4 %, and 11.2 %, respectively, thereby enhancing its stability. In summary, the pharmacophore model constructed in this study was accurate. The flavonoids Diosmetin, Fisetin, and Genistein effectively inhibited the activity of XO, and the amino acid residues LEU257, ILE353, and VAL259 played a key role in the interaction between the flavonoids and XO. These findings are of great significance for the screening and development of new XO inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The JAK-STAT signalling pathway is considered to be a significant role involved in the regulation of inflammatory diseases and immune responses, which indicate that specific inhibition of JAK-STAT pathway would be a potential key strategy for RA (Rheumatoid arthritis) treatment. Cedrol (CE), found from ginger by our group earlier, has been proven to play an excellent role in ameliorating RA via acting on JAK3. In this study, 27 new (1, 3-28), along with one known (2) derivatives of CE were synthesized by using chloroacetic acid and acryloyl chloride as intermediate ligands. In vitro, the inhibition effect on JAK kinases were performed using HTRF (Homogenous Time-Resolved Fluorescence) detection technology, which is more convenient and stable than traditional methods. The results compared with the secretion of LPS-induced p-JAK3 can better reflect the true kinase-selective effect of the compounds. Compound 22 was identified as a potent inhibitor to reduce the secretion of LPS-induced p-JAK3 with a dose-dependent manner. Given these results, compound 22 could serve as a favourable inhibitor of JAK3 for further research., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wei Li reports financial support was provided by Natural Science Foundation of Liaoning. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Peptidyl arginine deiminase 4 (PAD4) plays a critical role in many autoimmune diseases including rheumatoid arthritis. Herein, a trypsin assisted highly immunoassay method was established to determine PAD4 activity and screen potent inhibitors from herbal plants extracts and purified natural products. The method was applied to determine endogenous PAD4 activity in both cell and tissue lysates, as well as the inhibitory effects of 20 herbal plants and 50 purified natural products. The Cinnamomi ramulus extract showed strongest inhibitory potency with IC 50 value lower than 5 μg/mL. Meanwhile, pyrroloquinoline quinone (PQQ), widely used as a dietary supplement, was discovered as a promising PAD4 inhibitor with an IC 50 value lower than 4 μM. The inhibition kinetic analysis, drug affinity response target stability (DARTS) and molecular docking were performed to confirm the interaction between PQQ and PAD4. This method has great potential for researchers to monitor activities and discover potential inhibitors of PAD4., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alismatis Rhizoma (AR), a traditional Chinese medicine for treating obesity in traditional Chinese medicine clinic, is recognized as a promising source of lead compounds of lipase inhibitors. Ultrafiltration centrifugal combined with liquid chromatography-mass spectrometry (UF-LC-MS) was used for screening potential lipase inhibitors from AR, and the result indicated the binding capacity between compound 7 and lipase (92.3 ± 1.28 %) was significantly higher than other triterpenoids, and was identified as alisol C 23-acetate. It exhibited a mixed-type inhibitory behavior with an IC 50 value of 84.88 ± 1.03 μM. Subsequently, the binding pockets of alisol C 23-acetate to lipase were predicted, and their binding mechanism was explored with molecular simulation. Pocket 1 (active center) and pocket 4 might be the orthosteric and allosteric binding sites of alisol C 23-acetate to lipase, respectively. The interaction between alisol C 23-acetate and lipase was identified to involve key amino acid residues such as GLY-77, PHE-78, TYR-115, LEU-154, PRO-181, PHE-216, LEU-264, ASP-278, GLN-306, ARG-313, and VAL-426. Meanwhile, alisol C 23-acetate remained stable during the intestinal digestive but degraded in the gastric digestion. Overall, alisol C 23-acetate is expected to be the lead compound of lipase inhibitors for treating obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nipah virus (NiV) remains a significant global concern due to its impact on both the agricultural industry and human health, resulting in substantial economic and health consequences. Currently, there is no cure or commercially available vaccine for the virus. Therefore, it is crucial to prioritize the discovery of new and effective treatment options to prevent its continued spread. Streptomyces spp. are rich sources of metabolites known for their bioactivity against certain diseases; however, their potential as antiviral drugs against the Nipah virus remain unexplored. In this study, 6524 Streptomyces spp. metabolites were screened through in silico methods for their inhibitory effects against the Nipah virus matrix (NiV-M) protein, which assists in virion assembly of Nipah virus. Different computer-aided tools were utilized to carry out the virtual screening process: ADMET profiling revealed 913 compounds with excellent safety and efficacy profiles, molecular docking predicted the binding poses and associated docking scores of the ligands in their respective targets, MD simulations confirmed the binding stability of the top ten highest-scoring ligands in a 100 ns all-atom simulation, PCA elucidated simulation convergence, and MMPB(GB)SA calculations estimated the binding energies of the final candidate compounds and determined the key residues crucial for complex formation. Using in silico methods, we identified six metabolites targeting the main substrate-binding site and five targeting the dimerization site that exhibited excellent stability and strong binding affinity. We recommend testing these compounds in the next stages of drug development to confirm their effectiveness as therapeutic agents against Nipah virus., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cryptosporidiosis, a prevalent gastrointestinal illness worldwide, is caused by the protozoan parasite Cryptosporidium parvum. Calcium-dependent protein kinase 1 (CpCDPK1), crucial for the parasite's life cycle, serves as a promising drug target due to its role in regulating invasion and egress from host cells. While potent Pyrazolopyrimidine analogs have been identified as candidate hit molecules, they exhibit limitations in inhibiting Cryptosporidium growth in cell culture, prompting exploration of alternative scaffolds. Leveraging the most potent compound, RM-1-95, co-crystallized with CpCDPK1, an E-pharmacophore model was generated and validated alongside a deep learning model trained on known CpCDPK1 compounds. These models facilitated screening Enamine's 2 million HTS compound library for novel CpCDPK1 inhibitors. Subsequent hierarchical docking prioritized hits, with final selections subjected to Quantum polarized docking for accurate ranking. Results from docking studies and MD simulations highlighted similarities in interactions between the cocrystallized ligand RM-1-95 and identified hit molecules, indicating comparable inhibitory potential against CpCDPK1. Furthermore, assessing metabolic stability through Cytochrome 450 site of metabolism prediction offered crucial insights for drug design, optimization, and regulatory approval processes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Exploring more efficient pancreatic cancer drug screening platforms is of significant importance for accelerating the drug development process. In this study, we developed a high-sensitivity bioluminescence system based on smartphones and smart tablets, and constructed a pancreatic cancer drug screening platform (PCDSP) by combining the pancreatic cancer cell sensing model (PCCSM) on the multiwell plates (MTP). A smart tablet was used as the light source and a smartphone as the colorimetric sensing device. The smartphone dynamically controls the color and brightness displayed on the smart tablet to achieve lower LOD and wider detection ranges. We constructed PCCSM for 24 h, 48 h, and 72 h , and performed colorimetric experiments using both PCDSP and a commercial plate reader (CPR). The results showed that the PCDSP had a lower LOD than that of CPR. Moreover, PCDSP even exhibited a lower LOD for 24 h PCCSM testing compared to CPR for 48 h PCCSM testing, effectively shortening the drug evaluation process. Additionally, the PCDSP offers higher portability and efficiency compared with CPR, making it a promising platform for efficient pancreatic cancer drug screening., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD) and Kaposi's sarcoma (KS). KSHV is one of the oncoviruses that contribute to 1.5 million new infection-related cancer cases annually. Currently, there are no targeted therapies for KSHV-associated diseases. Through the development of a medium-throughput phenotype-based ELISA screening platform based on KSHV ORF57 protein detection, we screened the Medicines for Malaria Venture (MMV) Pandemic Response Box for non-cytotoxic inhibitors of KSHV lytic replication. MMV1645152 was identified as a promising inhibitor of KSHV lytic replication, suppressing KSHV immediate-early and late lytic gene expression and blocking the production of infectious KSHV virion particles at non-cytotoxic concentrations in cell line models of KSHV infection with or without EBV coinfection. MMV1645152 is a promising hit compound for the development of future therapeutic agents against KSHV-associated malignancies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Dysregulation of peptidyl arginine deiminase 4 (PAD4) is involved in a variety of diseases including rheumatoid arthritis (RA) and Alzheimer's disease (AD), and it has emerged as potential and promising therapeutic target. However, no PAD4 inhibitor is ready for clinical use. Immobilized enzyme screening technology has gained increasing attention due to its low cost, reusability, easy separation from the reaction mixture, and resistance to changes in environmental conditions. In this study, PAD4 was immobilized on the magnetic nanoparticles (MNP) to prolong its activity stability, and a simple and rapid screening strategy of traditional Chinese medicine inhibitors based on immobilized PAD4 was established. The PAD4 enzyme was immobilized on magnetic nanoparticles (MNP) via Schiff base reaction using glutaraldehyde (GA) as crosslinking agent. Compared with free PAD4, the resulting MNP@GA@PAD4 exhibited an enhanced tolerance to temperature and storage stability, and its reusability was greatly improved with 66 % of initial enzyme activity after being recycled 10 times. The inhibitory activity of the immobilized PAD4 was assessed using two known PAD4 inhibitors GSK484 and BB-Cl-amidine. The semi-maximum inhibitory concentrations (IC 50 ) of GSK484 and BB-Cl-amidine for MNP@GA@PAD4 were 1.00 and 0.97 μM, respectively, for free PAD4 were 0.64 and 0.85 μM, respectively. Finally, the MNP@GA@PAD4 was employed to rapid screen of natural PAD4 inhibitors from forty traditional Chinese medicines (TCMs). Under the same conditions, the controlled experiment was conducted with free PAD4. The screening results of TCMs inhibitors on MNP@GA@PAD4 and free PAD4 were similar, the alcohol extracts of Cinnamomi Cortex and Caryophylli Flos had significant inhibitory effects on PAD4 enzyme activity. The IC 50 values of Cinnamomi Cortex extract for MNP@GA@PAD4 and free PAD4 were determined as 27 and 48 μg/mL, respectively. The IC 50 values of Caryophylli Flos extracts for MNP@GA@PAD4 and free PAD4 were determined as 48 and 32 μg/mL, respectively. For the first time, this study proposed a method to immobilize PAD4 on magnetic materials, and developed a rapid, reusable and feasible strategy to screening natural PAD4 inhibitors from TCMs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acetyl-coenzyme A carboxylase (ACC) and diacylglycerol acyltransferase 2 (DGAT2) are recognized as potential therapeutic targets for nonalcoholic fatty liver disease (NAFLD). Inhibitors targeting ACC and DGAT2 have exhibited the capacity to reduce hepatic fat in individuals afflicted with NAFLD. However, there are no reports of dual inhibitors targeting ACC and DGAT2 for the treatment of NAFLD. Here, we aimed to identify potential dual inhibitors of ACC and DGAT2 using an integrated in silico approach. Machine learning-based virtual screening of commercial molecule databases yielded 395,729 hits, which were subsequently subjected to molecular docking aimed at both the ACC and DGAT2 binding sites. Based on the docking scores, nine compounds exhibited robust interactions with critical residues of both ACC and DGAT2, displaying favorable drug-like features. Molecular dynamics simulations (MDs) unveiled the substantial impact of these compounds on the conformational dynamics of the proteins. Furthermore, binding free energy assessments highlighted the notable binding affinities of specific compounds (V003-8107, G340-0503, Y200-1700, E999-1199, V003-6429, V025-4981, V006-1474, V025-0499, and V021-8916) to ACC and DGAT2. The compounds proposed in this study, identified using a multifaceted computational strategy, warrant experimental validation as potential dual inhibitors of ACC and DGAT2, with implications for the future development of novel drugs targeting NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Preclinical models of addictive drugs have been developed for decades to model aspects of the clinical experience in substance use disorders (SUDs). These include passive exposure as well as volitional intake models across addictive drugs and have been utilized to also measure withdrawal symptomatology and potential neurobehavioral mechanisms underlying relapse to drug seeking or taking. There are a number of Food and Drug Administration (FDA)-approved medications for SUDs, however, many demonstrate low clinical efficacy as well as potential sex differences, and we also note gaps in the continuum of care for certain aspects of clinical experiences in individuals who use drugs. In this review, we provide a comprehensive update on both frequently utilized and novel behavioral models of addiction with a focus on translational value to the clinical experience and highlight the need for preclinical research to follow epidemiological trends in drug use patterns to stay abreast of clinical treatment needs. We then note areas in which models could be improved to enhance the medications development pipeline through efforts to enhance translation of preclinical models. Next, we describe neuroscience efforts that can be leveraged to identify novel biological mechanisms to enhance medications development efforts for SUDs, focusing specifically on advances in brain transcriptomics approaches that can provide comprehensive screening and identification of novel targets. Together, the confluence of this review demonstrates the need for careful selection of behavioral models and methodological parameters that better approximate the clinical experience combined with cutting edge neuroscience techniques to advance the medications development pipeline for SUDs., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Antivirulence strategy has been explored as an alternative to traditional antibiotic development. The bacterial type IV pilus is a virulence factor involved in host invasion and colonization in many antibiotic resistant pathogens. The PilB ATPase hydrolyzes ATP to drive the assembly of the pilus filament from pilin subunits. We evaluated Chloracidobacterium thermophilum PilB (CtPilB) as a model for structure-based virtual screening by molecular docking and molecular dynamics (MD) simulations. A hexameric structure of CtPilB was generated through homology modeling based on an existing crystal structure of a PilB from Geobacter metallireducens. Four representative structures were obtained from molecular dynamics simulations to examine the conformational plasticity of PilB and improve docking analyses by ensemble docking. Structural analyses after 1 μs of simulation revealed conformational changes in individual PilB subunits are dependent on ligand presence. Further, ensemble virtual screening of a library of 4234 compounds retrieved from the ZINC15 database identified five promising PilB inhibitors. Molecular docking and binding analyses using the four representative structures from MD simulations revealed that top-ranked compounds interact with multiple Walker A residues, one Asp-box residue, and one arginine finger, indicating these are key residues in inhibitor binding within the ATP binding pocket. The use of multiple conformations in molecular screening can provide greater insight into compound flexibility within receptor sites and better inform future drug development for therapeutics targeting the type IV pilus assembly ATPase., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cystic echinococcosis is a zoonotic infection caused by the larval stage of Echinococcus granulosus sensu lato. The disease is characterized by the long-term growth of cysts, most commonly in the liver and lungs. Although an ideal model of cystic echinococcosis should induce the development of cysts in the liver and imitate the natural infection route, the murine model of intraperitoneal is still widely used in the field of experimental theraphy. The aim of the present work was to evaluate the usefulness of the murine model of hepatic CE for preclinical drug trials. The effectiveness of albendazole could also be assessed by measuring the diameter of the hepatic cyst. The albendazole significantly reduced the size of the cysts. The ultrastructural alterations of the germinal layer of hepatic cysts provoked by albendazole coincided with those observed in the intraperitoneal model. Similar results were obtained with both albendazole doses. Therefore, the efficacy of albendazole nanocrystals in the murine model of hepatic cystic echinococcosis was carried out at albendazole doses of 25 mg/kg. The abdominal ultrasound allows us to assess the response of cysts to drugs only in a qualitative manner. Although the size of cysts in the albendazole nanocrystal group was not significantly lower than that observed with albendazole, at the ultrastructural level, a greater extent of damage was observed. The murine model of hepatic cystic echinococcosis can be effectively used for assessing the effect of novel formulations or compounds. The main advantage of this model is that cysts are located in the orthotopic organ, which resembles the location most commonly found in human cases. In future studies, the usefulness of the model for pharmacokinetics studies in hepatic cysts will be evaluated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Two important plant enzymes are 4-hydroxyphenylpyruvate dioxygenase (HPPD; EC 1.13.11.27), which is necessary for biosynthesis of plastoquinone and tocopherols, and phytoene dehydrogenase (PDS; EC 1.3.99.26), which plays an important role in colour rendering. Dual-target proteins that inhibit pigment synthesis will prevent resistant weeds and improve the spectral characteristics of herbicides. This study introduces virtual screening of pharmacophores based on the complex structure of the two targets. A three-dimensional database was established by screening 1,492,858 compounds based on the Lipinski principle. HPPD&PDS dual-target receptor-ligand pharmacophore models were then constructed, and nine potential dual-target inhibitors were obtained through pharmacophore modeling, molecular docking, and molecular dynamics simulations. Ultimately, ADMET prediction software yielded three compounds with high potential as dual-target herbicides. The obtained nine inhibitors were stable when combined with both HPPD and PDS proteins. This study offers guidance for the development of HPPD&PDS dual-target inhibitors with novel skeletons., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The overexpression of FGFR1 is thought to significantly contribute to the progression of triple-negative breast cancer (TNBC), impacting aspects such as tumorigenesis, growth, metastasis, and drug resistance. Consequently, the pursuit of effective inhibitors for FGFR1 is a key area of research interest. In response to this need, our study developed a hybrid virtual screening method. Utilizing KarmaDock, an innovative algorithm that blends deep learning with molecular docking, alongside Schrödinger's Residue Scanning. This strategy led us to identify compound 6, which demonstrated promising FGFR1 inhibitory activity, evidenced by an IC 50 value of approximately 0.24 nM in the HTRF bioassay. Further evaluation revealed that this compound also inhibits the FGFR1 V561M variant with an IC 50 value around 1.24 nM. Our subsequent investigations demonstrate that Compound 6 robustly suppresses the migration and invasion capacities of TNBC cell lines, through the downregulation of p-FGFR1 and modulation of EMT markers, highlighting its promise as a potent anti-metastatic therapeutic agent. Additionally, our use of molecular dynamics simulations provided a deeper understanding of the compound's specific binding interactions with FGFR1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Elevated levels of butyrylcholinesterase (BuChE) have the potential to be predictive in the timely detection and diagnosis of Alzheimer's disease (AD). By inhibiting of BuChE activity can raise acetylcholine levels and intervene AD processes. Therefore, BuChE as an important factor in treatment AD has been given more and more attention in clinical studies. Given the facts above, in this study, for precise monitoring of BuChE level changes and screening for possible butyrylcholinesterase inhibitor (BuChEI) for AD diagnosis and therapy, a near-infrared (NIR) fluorescence probe (NFP-BuChE) was created. The probe exhibits excellent sensitivity and selectivity for BuChE. NFP-BuChE has been successfully applied to the detection of endogenous BuChE levels in live cells, and we successfully constructed a screening system for BuChEI on cells and a novel natural efficient BuChEI (matrine) was discovered and identified, which significantly reduced BuChE activity and thus alleviated AD symptoms. Most importantly, for the first time, we measured the changes of BuChE levels in zebrafish (0-4 days) after fertilization, various organs of zebrafish, and AD zebrafish modeled by different concentrations of AlCl 3 by NFP-BuChE, and at the same time, we also validated the inhibitory effect of matrine on BuChE by NFP-BuChE in zebrafish. In addition, NFP-BuChE has also been successfully used to measure the changes of BuChE levels in the brains of AD mice. These findings imply that NFP-BuChE is a potentially useful molecular tool for screening possible natural BuChEI quickly and for monitoring changes in BuChE activity, and it is expected that more value will be explored in mice. In addition, matrine and its derivatives are promising options for future Alzheimer's disease treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The discovery of pancreatic lipase (PL) inhibitors is an essential route to develop new anti-obesity drugs. In this experiment, chitosan was used to add amino groups to cellulose filter paper (CFP) and then glutaraldehyde was used to covalently combine PL with amino-modified CFP through the Schiff base reaction. Under optimal immobilization conditions, CFP immobilized PL has a wide range of pH and temperature tolerance, as well as excellent reproducibility, reusability and storage stability. Subsequently, 26 natural products (NPs) were screened by immobilized PL with black tea extract having the highest inhibition rate. Three compounds with binding effects on PL (epigallocatechin gallate, theaflavin-3-gallate and theaflavin-3,3'-digallate) were captured. Molecular docking proved that these three compounds have a strong binding affinity for PL. Fluorescence spectra further revealed that theaflavin-3,3'-digallate could statically quench the intrinsic fluorescence of pancreatic lipase. The molecular docking and thermodynamic parameters indicated that electrostatic interaction was considered as the main interaction force between PL and theaflavin-3,3'-digallate. Finally, the potential anti-obesity targets and pathways of the three compounds were discussed through network pharmacology. This study not only proposes a simple and efficient method for screening PL inhibitors, but also sheds light on the anti-obesity mechanism of active compounds in black tea., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: As promising biomarkers of diabetes, α-glucosidase (α-Glu) and β-glucosidase (β-Glu) play a crucial role in the diagnosis and management of diseases. However, there is a scarcity of techniques available for simultaneously and sensitively detecting both enzymes. What's more, most of the approaches for detecting α-Glu and β-Glu rely on a single-mode readout, which can be affected by multiple factors leading to inaccurate results. Hence, the simultaneous detection of the activity levels of both enzymes in a single sample utilizing multiple-readout sensing approaches is highly attractive., Results: In this work, we constructed a facile sensing platform for the simultaneous determination of α-Glu and β-Glu by utilizing a luminescent covalent organic framework (COF) as a fluorescent indicator. The enzymatic hydrolysis product common to both enzymes, p-nitrophenol (PNP), was found to affect the fluorometric signal through an inner filter effect on COF, enhance the colorimetric response by intensifying the absorption peak at 400 nm, and induce changes in RGB values when analyzed using a smartphone-based color recognition application. By combining fluorometric/colorimetric measurements with smartphone-assisted RGB mode, we achieved sensitive and accurate quantification of α-Glu and β-Glu. The limits of detection for α-Glu were determined to be 0.8, 1.22, and 1.85 U/L, respectively. Similarly, the limits of detection for β-Glu were 0.16, 0.42, and 0.53 U/L, respectively., Significance: Application of the proposed sensing platform to clinical serum samples revealed significant differences in the two enzymes between healthy people and diabetic patients. Additionally, the proposed sensing method was successfully applied for the screening of α-Glu inhibitors and β-Glu inhibitors, demonstrating its viability and prospective applications in the clinical management of diabetes as well as the discovery of antidiabetic medications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which acts as a negative regulator of prostaglandin E2 (PGE2) levels and activity, represents a promising pharmacological target for promoting liver regeneration. In this study, we collected data on 15-PGDH homologous family proteins, their inhibitors, and traditional Chinese medicine (TCM) compounds. Leveraging machine learning and molecular docking techniques, we constructed a prediction model for virtual screening of 15-PGDH inhibitors from TCM compound library and successfully screened genistein as a potential 15-PGDH inhibitor. Through further validation, it was discovered that genistein considerably enhances liver regeneration by inhibiting 15-PGDH, resulting in a significant increase in the PGE2 level. Genistein's effectiveness suggests its potential as a novel therapeutic agent for liver diseases, highlighting this study's contribution to expanding the clinical applications of TCM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Xanthine oxidase (XO) is a typical target for hyperuricemia and gout, for which there are only three commercial xanthine oxidase inhibitors (XOIs): febuxostat, topiroxostat and allopurinol. However, these inhibitors have problems such as low bioactivity and several side effects. Therefore, the development of novel XOIs with high bioactivity for the treatment of hyperuricemia and gout is urgently needed. In this work we constructed a XO immobilized cellulose membrane colorimetric biosensor (XNCM) by the TEMPO oxidation, amide bond coupling and nitro blue tetrazolium chloride (NBT) loading method. As expected, the XNCM was able to detect xanthine, with high selectivity and sensitivity by colorimetric method with a distinctive color change from yellow to purple, which can be easily observed by the naked-eye in just 8 min without any complex instrumentation. In addition, the XNCM sensor performed screening of 21 different compounds and have been successfully pre-screened out XOIs with biological activity. Most importantly, the XNCM was able to quantitatively detect the IC 50 values of two commercial inhibitors (febuxostat and allopurinol). All the results confirmed that the XNCM is a simple and effective tool which can be used for the accelerated screening of XOIs and has the potential to uncover additional XOIs., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships. The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized 2H-chromenes were synthesized by reacting activated methylene with 5-(piperidin-1-ylsulfonyl)salicylaldehyde through one-step condensation followed by intramolecular cyclization. Virtual screening of the designed molecules on α-glucosidase enzymes (PDB: 3W37 and 3A4A) exhibited good binding affinity suggesting that these derivatives may be potential α-glucosidase inhibitors. In-vitro α-glucosidase activity was conducted firstly at 100 µg/mL, and the results demonstrated good inhibitory potency with values ranging from 90.6% to 96.3% compared to IP = 95.8% for Acarbose. Furthermore, the IC 50 values were determined, and the designed derivatives exhibited inhibitory potency less than 11 µg/mL. Surprisingly, two chromene derivatives 6 and 10 showed the highest potency with IC 50 values of 0.975 ± 0.04 and 0.584 ± 0.02 µg/mL, respectively, compared to Acarbose (IC 50 = 0.805 ± 0.03 µg/mL). Moreover, our work was extended to evaluate the in-vitro α-amylase and PPAR-γ activity as additional targets for diabetic activity. The results exhibited moderate activity on α-amylase and potency as PPAR-γ agonist making it a multiplet antidiabetic target. The most active 2H-chromenes 6 and 10 exhibited significant activity to PPAR-γ with IC 50 values of 3.453 ± 0.14 and 4.653 ± 0.04 µg/mL compared to Pioglitazone (IC 50 = 4.884±0.29 µg/mL) indicating that these derivatives improve insulin sensitivity by stimulating the production of small insulin-sensitive adipocytes. In-silico ADME profile analysis indicated compliance with Lipinski's and Veber's rules with excellent oral bioavailability properties. Finally, the docking simulation was conducted to explain the expected binding mode and binding affinity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC 50 against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

KRAS-G12C inhibitors has been made significant progress in the treatment of KRAS-G12C mutant cancers, but their clinical application is limited due to the adaptive resistance, motivating development of novel structural inhibitors. Herein, series of coumarin derivatives as KRAS-G12C inhibitors were found through virtual screening and rational structural optimization. Especially, K45 exhibited strong antiproliferative potency on NCI-H23 and NCI-H358 cancer cells harboring KRAS-G12C with the IC 50 values of 0.77 μM and 1.50 μM, which was 15 and 11 times as potent as positive drug ARS1620, respectively. Furthermore, K45 reduced the phosphorylation of KRAS downstream effectors ERK and AKT by reducing the active form of KRAS (KRAS GTP) in NCI-H23 cells. In addition, K45 induced cell apoptosis by increasing the expression of anti-apoptotic protein BAD and BAX in NCI-H23 cells. Docking studies displayed that the 3-naphthylmethoxy moiety of K45 extended into the cryptic pocket formed by the residues Gln99 and Val9, which enhanced the interaction with the KRAS-G12C protein. These results indicated that K45 was a potent KRAS-G12C inhibitor worthy of further study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Influenza A virus causes severe respiratory illnesses, especially in developing nations where most child deaths under 5 occur due to lower respiratory tract infections. The RIG-I protein acts as a sensor for viral dsRNA, triggering interferon production through K63-linked poly-ubiquitin chains synthesized by TRIM25. However, the influenza A virus's NS1 protein hinders this process by binding to TRIM25, disrupting its association with RIG-I and preventing downstream interferon signalling, contributing to the virus's evasion of the immune response., Methods: In our study we used structural-based drug designing, molecular simulation, and binding free energy approaches to identify the potent phytocompounds from various natural product databases (>100,000 compounds) able to inhibit the binding of NS1 with the TRIM25., Results: The molecular screening identified EA-8411902 and EA-19951545 from East African Natural Products Database, NA-390261 and NA-71 from North African Natural Products Database, SA-65230 and SA- 4477104 from South African Natural Compounds Database, NEA- 361 and NEA- 4524784 from North-East African Natural Products Database, TCM-4444713 and TCM-6056 from Traditional Chinese Medicines Database as top hits. The molecular docking and binding free energies results revealed that these compounds have high affinity with the specific active site residues (Leu95, Ser99, and Tyr89) involved in the interaction with TRIM25. Additionally, analysis of structural dynamics, binding free energy, and dissociation constants demonstrates a notably stronger binding affinity of these compounds with the NS1 protein. Moreover, all selected compounds exhibit exceptional ADMET properties, including high water solubility, gastrointestinal absorption, and an absence of hepatotoxicity, while adhering to Lipinski's rule., Conclusion: Our molecular simulation findings highlight that the identified compounds demonstrate high affinity for specific active site residues involved in the NS1-TRIM25 interaction, exhibit exceptional ADMET properties, and adhere to drug-likeness criteria, thus presenting promising candidates for further development as antiviral agents against influenza A virus infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sirtuin1 (SIRT1), an NAD + -dependent histone deacetylase, plays a crucial role in regulating molecular signaling pathways. Recently, inhibition of SIRT1 rather than its activation shows the therapeutic potential for central nervous system disorder, however, the discovered SIRT1 inhibitors remains limited. In this work, a dual recognition-based strategy was developed to screen SIRT1 inhibitors from natural resources in situ. This approach utilized a Ni-modified metal-organic framework (Ni@Tyr@UiO-66-NH 2 ) along with cell lysate containing an engineered His-tagged SIRT1 protein, eliminating the need for purified proteins, pure compounds, and protein immobilization. The high-performance Ni@Tyr@UiO-66-NH 2 was synthesized by modifying the surface of UiO-66-NH 2 with Ni 2+ ions to specifically capture His-tagged SIRT1 while persevering its enzyme activity. By employing dual recognition, in which Ni@Tyr@UiO-66-NH 2 recognized SIRT1 and SIRT1 recognized its ligands, the process of identifying SIRT1 inhibitors from complex matrix was vastly streamlined. The developed method allowed the efficient discovery of 16 natural SIRT1 inhibitors from Chinese herbs. Among them, 6 compounds were fully characterized, and suffruticosol A was found to have an excellent IC 50 value of 0.95 ± 0.12 μM. Overall, an innovative dual recognition-based strategy was proposed to efficiently identify SIRT1 inhibitors in this study, offering scientific clues for the development of drugs targeting CNS disorders., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, “A dual recognition-based strategy employing Ni-modified metal-organic framework for in situ screening of SIRT1 inhibitors from Chinese herbs”., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: In recent decades, numerous herbal products have been shown to have antihyperglycemic and beta cell-regenerative effects in animal studies. However, there is no clinical evidence that those products completely cure patients with type-1 diabetes (T1D). Therefore, it seems that most of the phytochemicals do not have a significant impact on human beta cells, and the results of experimental studies conducted on them may not be generalizable to the clinic., Purpose: The present work aims to review extensively the methods and results of preclinical studies on phytotherapy of T1D published in the last 10 years., Methods: This paper critically analyzes the designs of studies, treatment protocols, methods of diabetes induction, characteristics of the studied animals, clinical relevance, reproducibility of research, and other aspects related to conducting preclinical studies on T1D. We discussed limitations that make many of the results of these studies not generalizable to the clinic. Finally, some recommendations were given to improve studies on the phytotherapy of T1D to avoid misleading interpretations about the antidiabetic effect of herbal compounds., Conclusion: This paper can be considered a practical guide for researchers interested in the field of phytotherapy of T1D to increase the reliability, reproducibility, and validity of their preclinical studies., Competing Interests: Declaration of competing interest The authors declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Approximately 3.9 billion individuals are vulnerable to dengue infection, a prevalent cause of tropical diseases worldwide. Currently, no drugs are available for preventing or treating Flavivirus diseases, including Dengue, West Nile, and the more recent Zika virus. The highly conserved Flavivirus NS2B-NS3 protease, crucial for viral replication, is a promising therapeutic target. This study employed in-silico methodologies to identify novel and potentially effective anti-dengue small molecules. A pharmacophore model was constructed using an experimentally validated NS2B-NS3 inhibitor, with the Gunner Henry score confirming the model's validity. The Natural Product Activity and Species Source (NPASS) database was screened using the validated pharmacophore model, yielding a total of 60 hits against the NS2B-NS3 protease. Furthermore, the docking finding reveals that our newly identified compounds from the NPASS database have enhanced binding affinities and established significant interactions with allosteric residues of the target protein. MD simulation and post-MD analysis further validated this finding. The free binding energy was computed in terms of MM-GBSA analysis, with the total binding energy for compound 1 (-57.3 ± 2.8 and - 52.9 ± 1.9 replica 1 and 2) indicating a stronger binding affinity for the target protein. Overall, this computational study identified these compounds as potential hit molecules, and these findings can open up a new avenue to explore and develop inhibitors against Dengue virus infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Finding potent inhibitors of O-GlcNAc transferase (OGT) has proven to be a challenge, especially because the diversity of published inhibitors is low. The large majority of available OGT inhibitors are uridine-based or uridine-like compounds that mimic the main interactions of glycosyl donor UDP-GlcNAc with the enzyme. Until recently, screening of DNA-encoded libraries for discovering hits against protein targets was dedicated to a few laboratories around the world, but has become accessible to wider public with the recent launch of the DELopen platform. Here we report the results and follow-up of a DNA-encoded library screening by using the DELopen platform. This led to the discovery of two new hits with structural features not resembling UDP. Small focused libraries bearing those two scaffolds were made, leading to low micromolar inhibition of OGT and elucidation of their structure-activity relationship., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

High-throughput drug screening (HTDS) has significantly reduced the time and cost of new drug development. Nonetheless, contact-dependent cell-cell communication (CDCCC) may impact the chemosensitivity of tumour cells. There is a pressing need for low-cost single-cell HTDS platforms, alongside a deep comprehension of the mechanisms by which CDCCC affects drug efficacy, to fully unveil the efficacy of anticancer drugs. In this study, we develop a microfluidic chip for single-cell HTDS and evaluate the molecular mechanisms impacted by CDCCC using quantitative mass spectrometry-based proteomics. The chip achieves high-quality drug mixing and single-cell capture, with single-cell drug screening results on the chip showing consistency with those on the 96-well plates under varying concentration gradients. Through quantitative proteomic analysis, we deduce that the absence of CDCCC in single tumour cells can enhance their chemoresistance potential, but simultaneously subject them to stronger proliferation inhibition. Additionally, pathway enrichment analysis suggests that CDCCC could impact several signalling pathways in tumour single cells that regulate vital biological processes such as tumour proliferation, adhesion, and invasion. These results offer valuable insights into the potential connection between CDCCC and the chemosensitivity of tumour cells. This research paves the way for the development of single-cell HTDC platforms and holds the promise of advancing tumour personalized treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sodium-glucose co-transporter 2 (SGLT2) is one of the important targets against type II diabetes mellitus. A typical SGLT2 inhibitor acts by inhibiting glucose reabsorption, thus lowering the blood glucose level. Unlike SGLT1, SGLT2 is responsible for almost 90% glucose reabsorption from glomerular filtrate. The current SGLT2 inhibitors include gliflozins, often prescribed as second or third-line agents in diabetes mellitus. The SGLT2 inhibitors also benefit patients with heart and kidney disease. Due to instability issues with the natural O-aryl glycoside analogues C-glycoside analogues were developed and showed improved stability. Despite enhanced bioavailability and selectivity of newer derivatives, some serious side effects are associated with gliflozin analogues. At the present study, we applied in-silico approaches to find new glycomimetic compounds as potent SGLT2 inhibitors that could show improvement in side effects associated with current analogues. This work applied both ligand-based and structure-based drug approaches to find potential compounds. We developed a 3D-QSAR method to screen potential inhibitors from a library of ten thousand compounds and performed docking studies. The compounds were ranked based on predicted pIC50 and docking score. An initial screening of five thousand compounds was conducted, and the subsequently selected top 12 compounds were based on binding free energy calculations. These selected compounds were subjected to molecular dynamics (MD) simulations. Remarkably, our simulations identified nine compounds that exhibited significant and sustained binding affinity compared to the co-crystallized Empagliflozin. Collectively, considering the anticipated pharmacokinetic profiles and toxicity assessments, several of these compounds emerged as promising candidates for further in-depth evaluation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prerna Ganwir reports financial support was provided by Department of Science and Technology, India. There is no fanatical or other interest to declare amongst the co-authors If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The application of Artificial Intelligence (AI) to screen drug molecules with potential therapeutic effects has revolutionized the drug discovery process, with significantly lower economic cost and time consumption than the traditional drug discovery pipeline. With the great power of AI, it is possible to rapidly search the vast chemical space for potential drug-target interactions (DTIs) between candidate drug molecules and disease protein targets. However, only a small proportion of molecules have labelled DTIs, consequently limiting the performance of AI-based drug screening. To solve this problem, a machine learning-based approach with great ability to generalize DTI prediction across molecules is desirable. Many existing machine learning approaches for DTI identification failed to exploit the full information with respect to the topological structures of candidate molecules. To develop a better approach for DTI prediction, we propose GraphormerDTI, which employs the powerful Graph Transformer neural network to model molecular structures. GraphormerDTI embeds molecular graphs into vector-format representations through iterative Transformer-based message passing, which encodes molecules' structural characteristics by node centrality encoding, node spatial encoding and edge encoding. With a strong structural inductive bias, the proposed GraphormerDTI approach can effectively infer informative representations for out-of-sample molecules and as such, it is capable of predicting DTIs across molecules with an exceptional performance. GraphormerDTI integrates the Graph Transformer neural network with a 1-dimensional Convolutional Neural Network (1D-CNN) to extract the drugs' and target proteins' representations and leverages an attention mechanism to model the interactions between them. To examine GraphormerDTI's performance for DTI prediction, we conduct experiments on three benchmark datasets, where GraphormerDTI achieves a superior performance than five state-of-the-art baselines for out-of-molecule DTI prediction, including GNN-CPI, GNN-PT, DeepEmbedding-DTI, MolTrans and HyperAttentionDTI, and is on a par with the best baseline for transductive DTI prediction. The source codes and datasets are publicly accessible at https://github.com/mengmeng34/GraphormerDTI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

AapoA-I, the main protein of high-density lipoprotein, plays a key role in the biogenesis and atheroprotective properties of high-density lipoprotein. We showed previously that a naturally occurring apoA-I mutation, L178P, induces major defects in protein's structural integrity and functions that may underlie the increased cardiovascular risk observed in carriers of the mutation. Here, a library of marketed drugs (956 compounds) was screened against apoA-I[L178P] to identify molecules that can stabilize the normal conformation of apoA-I. Screening was performed by the thermal shift assay in the presence of fluorescent dye SYPRO Orange. As an orthogonal assay, we monitored the change in fluorescence intensity of 8-anilinonaphthalene-1-sulfonic acid upon binding on hydrophobic sites on apoA-I. Screening identified four potential structure correctors. Subsequent analysis of the concentration-dependent effect of these compounds on secondary structure and thermodynamic stability of WT apoA-I and apoA-I[L178P] (assessed by thermal shift assay and circular dichroism spectroscopy), as well as on macrophage viability, narrowed the potential structure correctors to two, the drugs atorvastatin and bexarotene. Functional analysis showed that these two compounds can restore the defective capacity of apoA-I[L178P] to promote cholesterol removal from macrophages, an important step for atheroprotection. Computational docking suggested that both drugs target a positively charged cavity in apoA-I, formed between helix 1/2 and helix 5, and make extensive interactions that could underlie thermodynamic stabilization. Overall, our findings indicate that small molecules can correct defective apoA-I structure and function and may lead to novel therapeutic approaches for apoA-I-related dyslipidemias and increased cardiovascular risk., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Gastric cancer (GC) is a highly heterogeneous disease featuring many various histological and molecular subtypes. Therefore, it is imperative to have well-characterized in vitro models for personalized treatment development. Gastric cancer patient-derived organoids (PDOs), re-capitulating in vivo conditions, exhibit high clinical efficacy in predicting drug sensitivity to facilitate the development of cancer precision medicine., Methods: PDOs were established from surgically resected GC tumor tissues. Histological and molecular characterization of PDOs and primary tissues were performed via IHC and sequencing analysis. We also conducted drug sensitivity tests using PDO cultures with five chemotherapeutic drugs and twenty-two targeted drugs., Results: We have successfully constructed a PDOs biobank that included EBV+, intestinal/CIN, diffuse/GS, mixed and Her2+ GC subtypes, and these PDOs captured the pathological and genetic characteristics of corresponding tumors and exhibited different sensitivities to the tested agents. In a clinical case study, we performed an additional drug sensitivity test for a patient who reached an advanced progressive stage after surgery. We discovered that the combination of napabucasin and COTI-2 exhibited a stronger synergistic effect than either drug alone., Conclusion: PDOs maintained the histological and genetic characteristics of original cancer tissues. PDOs biobank opens up new perspectives for studying cancer cell biology and personalized medicine as a preclinical study platform., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Repurposing drugs can significantly reduce the time and costs associated with drug discovery and development. However, many drug compounds possess intrinsic fluorescence, resulting in aberrations such as auto-fluorescence, scattering and quenching, in fluorescent high-throughput screening assays. To overcome these drawbacks, time-resolved technologies have received increasing attention. In this study, we have developed a rapid and efficient screening platform based on time-resolved emission spectroscopy in order to screen for inhibitors of the DNA repair enzyme, uracil-DNA glycosylase (UDG). From a database of 1456 FDA/EMA-approved drugs, sodium stibogluconate was discovered as a potent UDG inhibitor. This compound showed synergistic cytotoxicity against 5-fluorouracil-resistant cancer cells. This work provides a promising future for time-resolved technologies for high-throughput screening (HTS), allowing for the swift identification of bioactive compounds from previously overlooked scaffolds due to their inherent fluorescence properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The strategic and targeted use of an anesthetized canine cardiovascular model early in drug discovery enables a comprehensive cardiovascular and electrophysiological assessment of potential safety liabilities and guides compound selection prior to initiation of chronic toxicological studies. An ideal model would enable exposure-response relationships to guide safety margin calculations, have a low threshold to initiate, and have quick delivery of decision quality data. We have aimed to profile compounds with diverse mechanism of actions (MoAs) of "non-QT" cardiovascular drug effects and evaluate the ability of nonclinical in vivo cardiovascular models to detect clinically reported effects. The hemodynamic effects of 11 drugs (atropine, itraconazole, atenolol, ivabradine, milrinone, enalaprilat, fasudil, amlodipine, prazosin, amiloride, and hydrochlorothiazide) were profiled in an anesthetized dog cardiovascular model. Derived parameters included: heart rate, an index of left ventricular contractility, mean arterial pressure, systemic vascular resistance, and cardiac output. Species specific plasma protein data was generated (human, dog) and utilized to calculate free drug concentrations. Using the anesthetized dog cardiovascular model, 10 of the 11 drugs displayed the predicted changes in CV parameters based on their primary MoAs and corresponding clinically described effects. Interestingly but not unexpected, 1 of 11 failed to display their predicted CV pattern which is likely due to a delay in pharmacodynamic effect that is beyond the duration of the experimental model (hydrochlorothiazide). The analysis from the current study supports the strategic use of the anesthetized dog model early in the drug discovery process for a comprehensive cardiovascular evaluation with good translation to human., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

New pathogenic influenza virus strains are constantly emerging, posing a serious risk to both human health and economic growth. To effectively control the spread of this virus, there is an urgent need for early, rapid, sensitive, simple, and cost-effective detection technologies, as well as new and effective antiviral drugs. In this study, we have successfully achieved a significant milestone by successfully fusing the H7N9 influenza virus hemagglutinin (HA) protein with the nano-luciferase component, resulting in the development of a novel set of biosensors. This remarkable achievement marks the first instance of utilizing this biosensor technology for influenza antibody detection. Our biosensor technology also has the potential to facilitate the development of antiviral drugs targeting specific epitopes of the HA protein, providing a promising avenue for the treatment of H7N9 influenza virus infections. Furthermore, our biosensors have broad applications beyond H7N9 influenza virus detection, as they can be expanded for the detection of other pathogens and drug screening applications in the future. By providing a novel and effective solution to the detection and treatment of influenza viruses, our biosensors have the potential to revolutionize the field of infectious disease control., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: In the US, opioid treatment providers (OTPs) have wide latitude to perform urine drug screening (UDS) and discharge clients for positive results. OTP clients have identified randomized and directly observed UDS as potentially stigmatizing, but little research has examined the association between UDS modality and retention in OTPs., Methods: This cross-sectional study uses the 2016-2017 NDATSS wave among OTPs that administered methadone. The exposure was a 4-level variable based on whether OTPs had a high percentage (≥ 90% of clients) who experienced randomized, observed, both, or neither modality of UDS. The outcome was the proportion of clients retained in treatment 1 year or longer (long-term retention). Analyses were conducted using fractional logit regression with survey weighting and presented as percentages and 95% confidence intervals. We also present how policies for involuntary clinic discharge modify these effects., Results: 150 OTPs were eligible with a median of 310 clients. 40 (27%) OTPs did not highly utilize either randomized or observed UDS, 22 (15%) only highly utilized observed UDS, 42 (28%) only highly utilized randomized UDS and 46 (31%) utilized both practices on ≥ 90% of clients. Adjusted estimates for long-term retention ranged from 57.7% in OTPs that conducted both randomized and observed UDS on ≥ 90% of clients and 70.4% in OTPs that did not highly utilize these practices. Involuntary discharge may moderate this relationship., Conclusion: Findings showed an association between high utilization of randomized and observed UDS and decreased long-term retention, suggesting that UDS modality may impact long-term OTP retention., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pryce S. Michener reports financial support was provided by National Institute on Drug Abuse., (Copyright © 2023. Published by Elsevier B.V.)

In-vitro models are available in the literature for predicting the volume of distribution at steady-state (Vd ss ) of drugs. The mechanistic model refers to the tissue composition-based model (TCM), which includes important factors that govern Vd ss such as drug physiochemistry and physiological data. The recognized TCM published by Rodgers and Rowland (TCM-RR) and a subsequent adjustment made by Simulations Plus Inc. (TCM-SP) have been shown to be generally less accurate with neutral compared to ionized drugs. Therefore, improving these models for neutral drugs becomes necessary. The objective of this study was to propose a new TCM for improving the prediction of Vd ss for neutral drugs. The new TCM included two modifications of the published models (i) accentuate the effect of the blood-to-plasma ratio (BPR) that should cover permeated molecules across the biomembranes, which is lacking in these models for neutral compounds, and (ii) use a different approach to estimate the binding in tissues. The new TCM was validated with a large dataset of 202 commercial and proprietary compounds including preclinical and clinical data. All scenario datasets were predicted more accurately with the TCM-New, whereas all statistical parameters indicate that the TCM-New showed significant improvements in terms of accuracy over the TCM-RR and TCM-SP. Predictions of Vd ss were frequently more accurate for the TCM-new with 83% within twofold error versus only 50% for the TCM-RR. And more than 95% of the predictions were within threefold error and patient interindividual differences can be predicted with the TCM-New, greatly exceeding the accuracy of the published models. Overall, the new TCM incorporating BPR significantly improved the Vd ss predictions in animals and humans for neutral drugs, and, hence, has the potential to better support the drug discovery and facilitate the first-in-human predictions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Cardiovascular diseases are caused by hereditary factors, environmental conditions, and medication-related issues. On the other hand, the cardiotoxicity of drugs should be thoroughly examined before entering the market. In this regard, heart-on-chip (HOC) systems have been developed as a more efficient and cost-effective solution than traditional methods, such as 2D cell culture and animal models. HOCs must replicate the biology, physiology, and pathology of human heart tissue to be considered a reliable platform for heart disease modeling and drug testing. Therefore, many efforts have been made to find the best methods to fabricate different parts of HOCs and to improve the bio-mimicry of the systems in the last decade. Beating HOCs with different platforms have been developed and techniques, such as fabricating pumpless HOCs, have been used to make HOCs more user-friendly systems. Recent HOC platforms have the ability to simultaneously induce and record electrophysiological stimuli. Additionally, systems including both heart and cancer tissue have been developed to investigate tissue-tissue interactions' effect on cardiac tissue response to cancer drugs. In this review, all steps needed to be considered to fabricate a HOC were introduced, including the choice of cellular resources, biomaterials, fabrication techniques, biomarkers, and corresponding biosensors. Moreover, the current HOCs used for modeling cardiac diseases and testing the drugs are discussed. We finally introduced some suggestions for fabricating relatively more user-friendly HOCs and facilitating the commercialization process., Competing Interests: Declaration of competing interest There is no conflict of interest for this manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Antibiotic resistance continues to be a growing concern for global health, accentuating the need for novel antibiotic discoveries. Traditional methodologies in this field have relied heavily on extensive experimental screening, which is often time-consuming and costly. Contrastly, computer-assisted drug screening offers rapid, cost-effective solutions. In this work, we propose FIAMol-AB, a deep learning model that combines graph neural networks, text convolutional networks and molecular fingerprint techniques. This method also combines an attention mechanism to fuse multiple forms of information within the model. The experiments show that FIAMol-AB may offer potential advantages in antibiotic discovery tasks over some existing methods. We conducted some analysis based on our model's results, which help highlight the potential significance of certain features in the model's predictive performance. Compared to different models, ours demonstrate promising results, indicating potential robustness and versatility. This suggests that by integrating multi-view information and attention mechanisms, FIAMol-AB might better learn complex molecular structures, potentially improving the precision and efficiency of antibiotic discovery. We hope our FIAMol-AB can be used as a useful method in the ongoing fight against antibiotic resistance., Competing Interests: Declaration of competing interest The authors of this article declare no conflicts of interest. The authors have no financial or personal relationships with any individuals or organizations that could influence the research., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This appraisal of state-of-the-art manuscript highlights and expands upon the thoughts conveyed in the lecture of Dr. Jean-Pierre Valentin, recipient of the 2021 Distinguished Service Award of the Safety Pharmacology Society, given on the 2nd December 2021. The article reflects on the strengths, weaknesses, opportunities, and threats that surrounded the evolution of safety and secondary pharmacology over the last 3 decades with a particular emphasis on pharmaceutical drug development delivery, scientific and technological innovation, complexities of regulatory framework and people leadership and development. The article further built on learnings from past experiences to tackle constantly emerging issues and evolving landscape whilst being cognizant of the challenges facing these disciplines in the broader drug development and societal context., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors are employed by or on behalf of UCB Biopharma SRL and as such may have access to share / stocks options., (Copyright © 2023. Published by Elsevier Inc.)

Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell-driven malignancies. However, approved covalent BTK inhibitors (cBTKis) are associated with treatment limitations because of off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here, we describe the preclinical profile of pirtobrutinib, a potent, highly selective, noncovalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate binding region and shows no direct interaction with C481. Consequently, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKis, prevented Y551 phosphorylation in the activation loop. These data suggest that pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines, and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed that pirtobrutinib was highly selective for BTK in >98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained >100-fold selectivity over other tested kinases. Collectively, these findings suggest that pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical, and structural attributes with the potential to treat B-cell-driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Modulation of glutamate receptors has demonstrated anxiolytic and/or antidepressant effects in rodent stress models. The chick social-separation stress paradigm exposes socially raised aves to an isolation stressor which elicits distress vocalizations (DVocs) in an attempt to re-establish contact. The model presents a state of panic during the first 5 min followed by a state of behavioral despair during the last 60 to 90 min. Making it useful as a dual anxiolytic/antidepressant screening assay. Further research has identified the Black Australorp strain as a stress-vulnerable, treatment-resistant, and ketamine-sensitive genetic line. Utilizing this genetic line, we sought to evaluate modulation of glutamatergic receptors for potential anxiolytic and/or antidepressant effects. Separate dose-response studies were conducted for the following drugs: the AMPA PAM LY392098, the mGluR 5 antagonist MPEP, the mGluR 2/3 agonist LY404039, the mGluR 2/3 antagonist LY341495, and the mGluR 7 agonist AMN082. The norepinephrine α 2 agonist clonidine and the NMDA antagonist ketamine were included as comparison for anxiolytic (anti-panic) and antidepressant effects, respectively. As in previous studies, clonidine reduced DVoc rates during the first 5 min (attenuation of panic) and ketamine elevated DVoc rates (attenuation of behavioral despair) during the last 60 min of isolation. The mGluR 2/3 agonist LY404039 and the mGluR 5 antagonist MPEP decreased DVoc rates during the first 5 min of isolation indicative of anxiolytic effects like that of clonidine while the mGluR 7 agonist AMN082 elevated DVoc rates in the later hour of isolation, representative of antidepressant effects like that of ketamine. Collectively, these findings suggest that certain glutamate targets may be clinically useful in treating panic disorder and/or treatment-resistant depression., Competing Interests: Declaration of competing interest The authors of this study have no conflicts., (Published by Elsevier Inc.)