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1.
Anal Chim Acta ; 1338: 343583, 2025 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-39832854

RESUMEN

BACKGROUD: Biomimetic nanoplatforms based on membrane coating strategies have received increasing attention in the field of medical research. However, it cannot perform biomedical imaging screening, which is essential for real-time identification. As a rich source of new drug discovery, traditional Chinese medicine (TCM) has made important contributions to the treatment of many diseases. RESULLT: Therefore, a magnetic fluorescent bifunctional nanomaterial was developed for screening the active ingredients in Fuzi. The magnetic fluorescence nanoparticles Fe3O4@GO@RhB synthesized by one-step synthesis showed low toxicity, excellent fluorescence properties and fast magnetic separation. After coating the magnetic nanoparticle with cell membrane, the screening procedure was optimized with positive drug verapamil hydrochloride. Under the optimal conditions, the active ingredients in aconite were screened, and the three active ingredients were identified as benzoyl-mesaconine, benzoyl-aconine and benzoyl-hypacoitine by UPLC-MS/MS. In addition, in situ imaging technique was used to further verify the proliferative activity of the screened active ingredients. SIGNIFICANCE: The magnetic fluorescence bifunctional nanoplatform for cell membrane bionic screening combined with in situ imaging technology established in this paper not only can rapidly and effectively target screening and separation of active ingredients in TCM, but also provides a new platform for bioimaging screening.


Asunto(s)
Membrana Celular , Colorantes Fluorescentes , Nanopartículas de Magnetita , Humanos , Membrana Celular/química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Nanopartículas de Magnetita/química , Descubrimiento de Drogas , Materiales Biomiméticos/química , Rodaminas/química , Medicamentos Herbarios Chinos/química
2.
J Infect Public Health ; 18(2): 102636, 2025 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-39798213

RESUMEN

INTRODUCTION: Ebola virus (EBOV) is a highly lethal RNA virus that causes severe hemorrhagic fever in humans and non-human primates. The lack of effective treatment or vaccine for this pathogen poses a serious threat to a global pandemic. Therefore, it is imperative to explore new drugs and therapies to combat this life-threatening infection. MATERIALS AND METHODS: In this study, we employed in silico methods to assess the inhibitory activity of natural products from traditional Chinese medicine (TCM) against four EBOV proteins that are crucial for viral replication and assembly: VP40, VP35, VP30, and VP24. We performed molecular docking of TCM compounds with the EBOV proteins and screened them based on their docking scores, binding free energies, and pharmacokinetic properties. RESULTS: Our results pinpointed eight TCM compounds (TCM1797, TCM2872, TCM250, TCM2837, TCM2644, TCM4697, TCM2322, and TCM277) that exhibited superior efficacy in inhibiting all the EBOV proteins compared to the controls. These compounds interacted with key residues of the EBOV proteins through various types of bonds, such as hydrogen bonds, salt bridges, and π-π interactions, forming stable complexes that could disrupt the function of the EBOV proteins. These compounds were found to possess known antiviral activity, acceptable pharmacokinetic properties, and human usage history, which make them promising candidates for anti-EBOV drug development. Moreover, the molecular simulation analysis confirmed the binding stability, structural compactness, and residue flexibility properties of these compounds. Furthermore, the binding free energy results revealed that VP30-TCM2644, VP30-TCM4697, VP35-TCM2837, VP24-TCM250, and VP24-TCM277 complexes exhibit significant binding free energy values compared to the control ligands. Principal Component Analysis (PCA) and Free Energy Landscape (FEL) results revealed the trajectories' motion and conformational energy states. CONCLUSIONS: Our findings provide valuable insights into the molecular mechanisms driving the efficacy of TCM drugs against EBOV and suggest novel approaches for the development of anti-EBOV therapies.


Asunto(s)
Antivirales , Ebolavirus , Medicina Tradicional China , Simulación del Acoplamiento Molecular , Antivirales/farmacología , Antivirales/química , Antivirales/farmacocinética , Ebolavirus/efectos de los fármacos , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Descubrimiento de Drogas/métodos , Unión Proteica , Proteínas Virales/metabolismo , Proteínas Virales/química , Termodinámica
3.
Chin J Nat Med ; 23(1): 31-42, 2025 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-39855829

RESUMEN

Peptide-based therapies have attracted considerable interest in the treatment of cancer, diabetes, bacterial infections, and neurodegenerative diseases due to their promising therapeutic properties and enhanced safety profiles. This review provides a comprehensive overview of the major trends in peptide drug discovery and development, emphasizing preclinical strategies aimed at improving peptide stability, specificity, and pharmacokinetic properties. It assesses the current applications and challenges of peptide-based drugs in these diseases, illustrating the pharmaceutical areas where peptide-based drugs demonstrate significant potential. Furthermore, this review analyzes the obstacles that must be overcome in the future, aiming to provide valuable insights and references for the continued advancement of peptide-based drugs.


Asunto(s)
Péptidos , Humanos , Péptidos/uso terapéutico , Péptidos/química , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Animales , Diabetes Mellitus/tratamiento farmacológico , Infecciones Bacterianas/tratamiento farmacológico
4.
J Comput Chem ; 46(2): e70030, 2025 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-39797538

RESUMEN

Cyclooxygenase-2 (COX-2) is an enzyme that plays a crucial role in inflammation by converting arachidonic acid into prostaglandins. The overexpression of enzyme is associated with conditions such as cancer, arthritis, and Alzheimer's disease (AD), where it contributes to neuroinflammation. In silico virtual screening is pivotal in early-stage drug discovery; however, the absence of coding or machine learning expertise can impede the development of reliable computational models capable of accurately predicting inhibitor compounds based on their chemical structure. In this study, we developed an automated KNIME workflow for predicting the COX-2 inhibitory potential of novel molecules by building a multi-level ensemble model constructed with five machine learning algorithms (i.e., Logistic Regression, K-Nearest Neighbors, Decision Tree, Random Forest, and Extreme Gradient Boosting) and various molecular and fingerprint descriptors (i.e., AtomPair, Avalon, MACCS, Morgan, RDKit, and Pattern). Post-applicability domain filtering, the final majority voting-based ensemble model achieved 90.0% balanced accuracy, 87.7% precision, and 86.4% recall on the external validation set. The freely accessible workflow empowers users to swiftly and effortlessly predict COX-2 inhibitors, eliminating the need for any prior knowledge in machine learning, coding, or statistical modeling, significantly broadening its accessibility. While beginners can seamlessly use the tool as is, experienced KNIME users can leverage it as a foundation to build advanced workflows, driving further research and innovation.


Asunto(s)
Inhibidores de la Ciclooxigenasa 2 , Ciclooxigenasa 2 , Aprendizaje Automático , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/química , Humanos , Flujo de Trabajo , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Algoritmos , Estructura Molecular
5.
Inflamm Res ; 74(1): 2, 2025 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-39762416

RESUMEN

BACKGROUND: Traditional Chinese medicine (TCM) is a valuable resource for drug discovery and has demonstrated excellent efficacy in treating inflammatory diseases. This study aimed to develop a universal gene signature-based strategy for high-throughput discovery of anti-inflammatory drugs, especially Traditional Chinese medicine (TCM). METHODS: The disease gene signature of liposaccharide-stimulated THP-1 cells and drug gene signatures of 655 drug candidates were established via sequencing. Anti-inflammatory drugs were screened based on similarities between drug gene signatures and the reversed disease gene signature. RESULTS: Through screening, 83 potential anti-inflammatory drugs were identified. The efficacy of the TCM formula Biyun Powder, along with individual TCMs, Centipedea Herba, Kaempferiae Rhizoma, and Schizonepetae Spica Carbonisata, was verified in vitro or in vivo. Mechanistically, they exerted anti-inflammatory effects by inhibiting the nuclear factor-kappa B pathway. Kaempferol and luteolin were identified as bioactive IκB kinase-ß inhibitors in Kaempferiae Rhizoma and Schizonepetae Spica Carbonisata, respectively. CONCLUSION: We developed a universal gene signature-based approach for the high-throughput discovery of anti-inflammatory drugs that is applicable to compounds and to TCM herbs/formulae and established a workflow (screening, validation of efficacy, and identification of the mechanism of action and bioactive compounds) that can serve as a research template for high-throughput drug research.


Asunto(s)
Antiinflamatorios , Medicamentos Herbarios Chinos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Humanos , Animales , Medicamentos Herbarios Chinos/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , Células THP-1 , Medicina Tradicional China , Transcriptoma/efectos de los fármacos , Masculino , Ratones , Descubrimiento de Drogas/métodos , Lipopolisacáridos/farmacología , FN-kappa B/metabolismo , FN-kappa B/genética , Inflamación/tratamiento farmacológico , Inflamación/genética
6.
Eur J Med Chem ; 284: 117229, 2025 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-39826937

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease for which few drugs are available in clinical practice. Here, we identified novel capsaicin analogs by combining in-house chemical library screening and further structural optimization. (E)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (Compound 14) was found to be the most potent in inhibiting TGF-ß-induced collagen accumulation, proliferation and migration in fibroblast cells. Furthermore, compound 14 (IC50 = 0.51 ± 0.06 µM) showed over 100-fold increasing antifibrotic activity compared to capsaicin (IC50 = 53.71 ± 4.78 µM). Notably, compound 14 could target TRPV1, thereby affecting the expression of the fibrosis markers Collagen Ⅰ and α-SMA by inhibiting the TGF-ß/Smads and MAPK pathways to exert antifibrotic activity in vitro. Compound 14 significantly inhibited collagen deposition in lung tissues, ameliorated alveolar structures, and increased survival rates in mice with bleomycin-induced pulmonary fibrosis. In addition, compound 14 possessed lower cytotoxicity (compared to nitedanib) and no toxicity in mice. Overall, compound 14 promise as a potential drug candidate for the treatment of IPF.


Asunto(s)
Capsaicina , Proliferación Celular , Fibrosis Pulmonar Idiopática , Canales Catiónicos TRPV , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/patología , Animales , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Ratones , Capsaicina/farmacología , Humanos , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Bleomicina/farmacología , Ratones Endogámicos C57BL , Masculino , Fibroblastos/efectos de los fármacos
7.
Curr Opin Struct Biol ; 90: 102982, 2025 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-39827710

RESUMEN

Macromolecular X-ray crystallography allows detection and characterisation of the binding of small, low-affinity chemical fragments. Here we review the utility of fragment screening for drug discovery, its potential for use in discovery science, as well as some of the distinct types of fragments that have been compiled into libraries.


Asunto(s)
Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas , Cristalografía por Rayos X , Bibliotecas de Moléculas Pequeñas/química , Descubrimiento de Drogas/métodos , Humanos , Evaluación Preclínica de Medicamentos/métodos , Ligandos
8.
Methods Mol Biol ; 2895: 259-269, 2025.
Artículo en Inglés | MEDLINE | ID: mdl-39885035

RESUMEN

Known for their diverse and potent physiological activities, natural products continue to be essential for the discovery and development of new drugs. This chapter explores the pivotal role of preparative thin-layer chromatography (Prep-TLC) in the isolation of natural products. This chapter begins with an understanding of the historical significance and structural complexity of natural products, and discusses the problems caused by complex mixtures present in extracts, as well as the multifunctionality, cost-effectiveness, and compatibility with different sample types of Prep-TLC to address these challenges. We then explain the problems of separating these compounds and introduce Prep-TLC as a solution. The focus shifts to the fundamental principles and methodologies of Prep-TLC, highlighting its role in achieving the efficient separation and isolation of natural products. To illustrate the successful application of Prep-TLC to isolate bioactive compounds from various natural sources, real-world case and case studies are presented. In this chapter, we aim to provide practical assistance to researchers and practitioners by explaining the principles and methodologies of Prep-TLC that facilitate the discovery of novel physiologically active compounds.


Asunto(s)
Productos Biológicos , Productos Biológicos/aislamiento & purificación , Productos Biológicos/química , Cromatografía en Capa Delgada/métodos , Descubrimiento de Drogas/métodos , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Humanos
9.
J Agric Food Chem ; 73(1): 4-29, 2025 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-39644261

RESUMEN

Triterpenoids are the major active constituents of licorice, a well-known traditional medicinal herb. Licorice triterpenoids, represented by glycyrrhizin and glycyrrhetic acid, have a high structural diversity and are excellent lead compounds for the development of potent pharmaceuticals. However, their further application can be limited by insufficient activities, low bioavailability, and the presence of side effects, as well as the inefficiency of traditional plant extraction processes for compound production. To address these issues, researchers are focusing on rare triterpenoid components in the genus Glycyrrhiza and developing derivatives to preserve or enhance the original physiological activities with improved bioavailability and reduced side effects. At the same time, synthetic biology offers opportunities to shorten the production cycle, create eco-friendly manufacturing processes, and reduce the cost of producing licorice triterpenoids. Although much progress has been achieved in this field in recent years, there is still a lack of a comprehensive review to summarize the overall characteristics of licorice triterpenoids rather than glycyrrhizin and glycyrrhetinic acid. Based on this, our review comprehensively outlines the structures, origins, and pharmacological activities of licorice triterpenoids and predicts their pharmacological activities using the drugCIPHER algorithm. Furthermore, this paper reviews the advances and strategies for the biomanufacturing of licorice triterpenoids using synthetic biology methods and outlines the perspectives and structure-activity relationships for the derivatization of licorice triterpenoids. This review provides new insights into the discovery and synthesis of pharmaceuticals derived from natural triterpenes.


Asunto(s)
Glycyrrhiza , Triterpenos , Glycyrrhiza/química , Triterpenos/química , Humanos , Extractos Vegetales/química , Animales , Descubrimiento de Drogas , Estructura Molecular , Ácido Glicirrínico/química
10.
Nucleic Acids Res ; 53(D1): D1322-D1327, 2025 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-39441070

RESUMEN

The rational design of targeted covalent inhibitors (TCIs) has emerged as a powerful strategy in drug discovery, known for its ability to achieve strong binding affinity and prolonged target engagement. However, the development of covalent drugs is often challenged by the need to optimize both covalent warhead and non-covalent interactions, alongside the limitations of existing compound libraries. To address these challenges, we present CovalentInDB 2.0, an updated online database designed to support covalent drug discovery. This updated version includes 8303 inhibitors and 368 targets, supplemented by 3445 newly added cocrystal structures, providing detailed analyses of non-covalent interactions. Furthermore, we have employed an AI-based model to profile the ligandability of 144 864 cysteines across the human proteome. CovalentInDB 2.0 also features the largest covalent virtual screening library with 2 030 192 commercially available compounds and a natural product library with 105 901 molecules, crucial for covalent drug screening and discovery. To enhance the utility of these compounds, we performed structural similarity analysis and drug-likeness predictions. Additionally, a new user data upload feature enables efficient data contribution and continuous updates. CovalentInDB 2.0 is freely accessible at http://cadd.zju.edu.cn/cidb/.


Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas , Ligandos , Humanos , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Cisteína/química , Bases de Datos de Compuestos Químicos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Proteoma/química
11.
J Neurochem ; 169(1): e16289, 2025 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-39680493

RESUMEN

Preclinical behavioral testing is essential for drug discovery in neuropsychiatric disorders, yet translational challenges persist because of interspecies differences. Touchscreen-based behavioral tasks offer a promising solution for bridging this gap. These tasks provide flexibility across cognitive domains and species, facilitating rigorous comparisons. They complement traditional assays, offering improved face, predictive, and construct validity by mirroring human neuropsychological tests. Notably, nearly identical tasks have been validated in multiple species, enhancing translational potential. Recent studies demonstrate conserved neurocircuitry engagement in touchscreen tasks, supporting their relevance to human function and therapeutic development. The integration of electrophysiological measures, such as electroencephalography (EEG) and local field potential (LFP) recordings with touchscreen behavioral assays, enhances translational biomarker discovery and serves to elucidate neural circuit dynamics. Despite current limitations and the need for further validation, this approach offers a pathway to more efficient drug discovery. This review covers recent research describing the feasibility and benefits of EEG/LFP-touchscreen combination studies in rodents. While the field is still in its early stages, the promise of this research strategy is evident. Future efforts will likely focus on refining methodologies, identifying robust translational biomarkers, and expanding studies across species. Touchscreen-based platforms, integrated with electrophysiological measurements, hold significant potential to advance our understanding of neuropsychiatric disorders and accelerate the development of effective treatments.


Asunto(s)
Descubrimiento de Drogas , Electroencefalografía , Animales , Descubrimiento de Drogas/métodos , Electroencefalografía/métodos , Roedores , Humanos , Neurociencias/métodos , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Evaluación Preclínica de Medicamentos/métodos
12.
SLAS Technol ; 29(6): 100228, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39638256

RESUMEN

The purpose of this study was to examine the therapeutic potential of core traditional Chinese medicine (CTCM) in the treatment of diabetic peripheral neuropathy (DPN) through the use of a data-driven approach that combined network pharmacology and data mining. Important components of traditional Chinese medicine (TCM) and the targets that correspond with them were found through the examination of numerous databases and clinical prescriptions. The possible therapeutic pathways were investigated, with an emphasis on the AGE-RAGE pathway that was discovered via network pharmacology analysis. By evaluating histopathological alterations, inflammatory and apoptotic markers, microcirculation, and blood hypercoagulability in a rat model of DPN, the effectiveness of CTCM was confirmed.Through experimental validation in DPN rats, it was shown that CTCM improved histopathology, decreased inflammation and apoptosis, improved microcirculation, and corrected coagulation abnormalities in addition to alleviating neuropathic pain. These studies show the value of data-driven approaches in advancing traditional medicine research for drug development and offer a mechanistic basis for CTCM's therapeutic potential in DPN.


Asunto(s)
Minería de Datos , Neuropatías Diabéticas , Descubrimiento de Drogas , Medicina Tradicional China , Farmacología en Red , Animales , Neuropatías Diabéticas/tratamiento farmacológico , Ratas , Medicamentos Herbarios Chinos/farmacología , Modelos Animales de Enfermedad , Humanos , Masculino
13.
PLoS One ; 19(12): e0311527, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39652601

RESUMEN

The epidermal growth factor receptor (EGFR), a crucial component of cellular signaling pathways, is frequently dysregulated in a range of cancers. EGFR targeting has become a viable approach in the development of anti-cancer medications. This study employs an integrated approach to drug discovery, combining multiple computational methodologies to identify potential EGFR inhibitors. The co-crystal ligand for the EGFR protein (R85) (PDB ID: 7AEI) was employed as a model for developing pharmacophore hypotheses. Nine databases underwent a ligand-based virtual screening, and 1271 hits meeting the screening criteria were chosen. EGFR protein crystal structure was obtained from the PDB database (PDB ID: 7AEI) and prepared. The hit compounds identified during virtual screening were docked to the prepared EGFR receptor to predict binding affinities by using the glide tool's standard precision mode. The top ten compounds were chosen, and their affinities of binding ranged from -7.691 to -7.338 kcal/mol. The ADMET properties of the selected compounds were predicted, and three compounds MCULE-6473175764, CSC048452634, and CSC070083626 showed better QPPCaco values compared to other identified compounds, so these were selected for further stability analysis. To confirm the stability of the protein-ligand complexes, a 200 ns molecular dynamics (MD) simulation was run using the binding sites of the top three compounds against the EGFR receptor. These results suggest that the selected compounds may be lead compounds in suppressing the biological activity of EGFR, additional experimental investigation is required.


Asunto(s)
Descubrimiento de Drogas , Receptores ErbB , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Receptores ErbB/química , Descubrimiento de Drogas/métodos , Humanos , Ligandos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Unión Proteica , Evaluación Preclínica de Medicamentos/métodos , Farmacóforo
14.
PLoS One ; 19(12): e0315245, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39729480

RESUMEN

The increasing utilization of deep learning models in drug repositioning has proven to be highly efficient and effective. In this study, we employed an integrated deep-learning model followed by traditional drug screening approach to screen a library of FDA-approved drugs, aiming to identify novel inhibitors targeting the TNF-α converting enzyme (TACE). TACE, also known as ADAM17, plays a crucial role in the inflammatory response by converting pro-TNF-α to its active soluble form and cleaving other inflammatory mediators, making it a promising target for therapeutic intervention in diseases such as rheumatoid arthritis. Reference datasets containing active and decoy compounds specific to TACE were obtained from the DUD-E database. Using RDKit, a cheminformatics toolkit, we extracted molecular features from these compounds. We applied the GraphConvMol model within the DeepChem framework, which utilizes graph convolutional networks, to build a predictive model based on the DUD-E datasets. Our trained model was subsequently used to predict the TACE inhibitory potential of FDA-approved drugs. From these predictions, Vorinostat was identified as a potential TACE inhibitor. Moreover, molecular docking and molecular dynamics simulation were conducted to validate these findings, using BMS-561392 as a reference TACE inhibitor. Vorinostat, originally an FDA-approved drug for cancer treatment, exhibited strong binding interactions with key TACE residues, suggesting its repurposing potential. Biological evaluation with RAW 264.7 cell confirmed the computational results, demonstrating that Vorinostat exhibited comparable inhibitory activity against TACE. In conclusion, our study highlights the capability of deep learning models to enhance virtual screening efforts in drug discovery, efficiently identifying potential candidates for specific targets such as TACE. Vorinostat, as a newly identified TACE inhibitor, holds promise for further exploration and investigation in the treatment of inflammatory diseases like rheumatoid arthritis.


Asunto(s)
Proteína ADAM17 , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Proteína ADAM17/antagonistas & inhibidores , Proteína ADAM17/metabolismo , Ratones , Animales , Aprendizaje Profundo , Reposicionamiento de Medicamentos/métodos , Vorinostat/farmacología , Humanos , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos
15.
SLAS Discov ; 29(8): 100198, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39622293

RESUMEN

Target-based screening of covalent fragment libraries with mass spectrometry has emerged as a powerful strategy to identify chemical starting points for small molecule inhibitors or find new binding pockets on proteins of interest. These libraries span diverse chemical space with a modest number of compounds. Screening covalent fragments against purified protein targets reduces the demands on the mass spectrometer with respect to absolute throughput, detection limit, and dynamic range. Given these relaxed analytical requirements, we sought to develop an open-source, medium-throughput mass spectrometry system for target-based covalent fragment screening. Our platform comprises automated, dual LC desalting columns integrated with electrospray ionization for rapid sample introduction and mass spectrometry detection. The system is operated through a simple Python graphical user interface running on commodity microcontroller boards which allow integration with diverse liquid chromatography and mass spectrometry instruments. We provide scripts for fragment pooling, construction of sample batches, along with routines for data processing and visualization. The system enables primary screening of ∼10,000 covalent fragments per day in pooled format. In a proof-of-concept study we executed primary and secondary screens to identify 27 hit fragments against UCHL1, a deubiquitinating enzyme that is emerging as a drug target of interest across multiple clinical indications. We validated and triaged these covalent compounds through a series of orthogonal biochemical and chemoproteomic assays. The most promising chloroacetamide covalent fragment inhibited UCHL1 activity in vitro (IC50 < 5 µM) and exhibited dose-dependent binding along with good selectivity against 57 cellular DUBs as quantified by activity-based protein profiling.


Asunto(s)
Bibliotecas de Moléculas Pequeñas , Ubiquitina Tiolesterasa , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Humanos , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Descubrimiento de Drogas/métodos , Cromatografía Liquida/métodos , Espectrometría de Masas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Evaluación Preclínica de Medicamentos/métodos
16.
Arch Microbiol ; 207(1): 18, 2024 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-39724243

RESUMEN

Klebsiella pneumoniae is a leading cause of anti-microbial resistance in healthcare-associated infections that have posed a severe threat to neonatal and wider community. The escalating crises of antibiotic resistance have compelled researchers to explore an innovative arsenal beginning from natural resources to chemical modifications in order to overcome the ever-increasing resistance issues. The present review highlights the drug discovery efforts with a special focus on cutting-edge strategies in the hunt for potential drug candidates against MDR/XDR Klebsiella pneumoniae. Nature's bounty constituting plant extracts, essential oils, fungal extracts, etc. holds promising anti-bacterial potential especially when combined with existing antibiotics. Further, enhancing these natural products with synthetic moieties has improved their effectiveness, creating a bridge between the natural and synthetic world. Conversely, the synthetically modified novel scaffolds have been also designed to meticulously target specific sites. Furthermore, we have also elaborated various emerging strategies for broad-spectrum infections caused by K. pneumoniae, which include anti-microbial peptides, nanotechnology, drug repurposing, bacteriophage, photodynamic, and multidrug therapies. This review further addresses the challenges confronted by the research community and the future way forward in the field of drug discovery against multi-resistant bacterial infections.


Asunto(s)
Antibacterianos , Farmacorresistencia Bacteriana Múltiple , Infecciones por Klebsiella , Klebsiella pneumoniae , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/efectos de los fármacos
17.
Sci Rep ; 14(1): 31039, 2024 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-39730767

RESUMEN

Continued efforts to discover new antibacterial molecules are critical to achieve a robust pre-clinical pipeline for new antibiotics. Screening of compound or natural product extract libraries remains a widespread approach and can benefit from the development of whole cell assays that are robust, simple and versatile, and allow for high throughput testing of antibacterial activity. In this study, we created and validated two bioluminescent reporter strains for high-throughput screening, one in Pseudomonas aeruginosa, and another in a hyperporinated and efflux-deficient Escherichia coli. We show that the bioluminescent strains have a large dynamic range that closely correlates with cell viability and is superior to conventional optical density (OD600) measurements, can detect dose-dependent antibacterial activity and be used for different drug discovery applications. We evaluated the assays' performance characteristics (signal to background ratio, signal window, Z' robust) and demonstrated their potential utility for antibiotic drug discovery in two examples. The P. aeruginosa bioluminescent reporter was used in a pilot screen of 960 repurposed compound libraries to identify adjuvants that potentiate the fluoroquinolone antibiotic ofloxacin. The E. coli bioluminescent reporter was used to test the antibacterial activity of bioactive bacterial supernatants and assist with bioassay-guided fractionation of the crude extracts.


Asunto(s)
Antibacterianos , Escherichia coli , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa , Pseudomonas aeruginosa/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Mediciones Luminiscentes/métodos , Evaluación Preclínica de Medicamentos/métodos , Descubrimiento de Drogas/métodos
18.
Open Vet J ; 14(9): 2192-2214, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39553769

RESUMEN

Background: Porcine epidemic diarrhea virus (PEDV) is a recurring coronavirus that causes severe diarrhea in pigs with high mortality and morbidity rates, especially in neonatal pigs. Despite the availability of vaccines, their efficacy is limited owing to antigenic differences between the vaccine and field strains, which poses a challenge to infection control. Antiviral drugs targeting conserved PEDV proteins show promise for complementing vaccination strategies. PEDV Nsp3 (PL2Pro) and Nsp5 (3CLPro) are essential proteases vital for viral replication, making them attractive targets for drug development against PEDV. Aim: To address the lack of therapeutics against recurring PEDV outbreaks and bridge the gap in the application of bioinformatics in veterinary drug discovery, this study aimed to discover compounds that inhibit PEDV proteases from Philippine medicinal plants by applying a modified virtual screening methodology that considers the physiology of swine hosts. Methods: This study employed a library of 690 metabolites from Philippine medicinal plants to screen for potential protease inhibitors targeting PEDV PL2Pro and 3CLPro. This includes evaluating the binding affinity, pharmacokinetics, dynamic stability, and critical binding site residues. Compounds demonstrating high affinity underwent a modified ADMET analysis, considering the enteric localization of the virus and potential toxicity to swine hosts. Furthermore, molecular dynamics simulations assessed compound stability under physiological swine conditions. Results: The study identified Bisandrographolide from Andrographis paniculata, CID 162866964 from Euphorbia neriifolia, and betulinic acid from Vitex negundo and Ocimum basilicum as metabolites that bind favorably and selectively to PEDV 3CLPro and have excellent pharmacokinetic properties and dynamic stability. In contrast, no selective inhibitor for PL2pro passed the same criteria. Conclusion: Employing the modified virtual screening protocol tailored for swine host considerations, the compounds identified in this study are anticipated to exert inhibitory effects against PEDV without off-target binding to analogous swine proteases and receptors. CID 162866964, bisandrographolide, and betulinic acid show promise for developing potent antivirals against PEDV.


Asunto(s)
Infecciones por Coronavirus , Descubrimiento de Drogas , Plantas Medicinales , Virus de la Diarrea Epidémica Porcina , Inhibidores de Proteasas , Virus de la Diarrea Epidémica Porcina/efectos de los fármacos , Animales , Plantas Medicinales/química , Inhibidores de Proteasas/farmacología , Porcinos , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Antivirales/farmacología , Enfermedades de los Porcinos/virología , Enfermedades de los Porcinos/tratamiento farmacológico , Filipinas , Metabolismo Secundario , Simulación del Acoplamiento Molecular
19.
World J Gastroenterol ; 30(41): 4411-4416, 2024 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-39534414

RESUMEN

This editorial offers an updated synthesis of the major advancements in the management and treatment of inflammatory bowel disease (IBD), as documented in the World Journal of Gastroenterology between 2023 and early 2024. This editorial explores substantial developments across key research areas, such as intestinal microecology, computational drug discovery, dual biologic therapy, telemedicine, and the integration of lifestyle changes into patient care. Furthermore, the discussion of emerging topics, including bowel preparation in colonoscopy, the impact of the coronavirus disease 2019 pandemic, and the intersection between IBD and mental health, reflects a shift toward a more holistic approach to IBD research. By integrating these diverse areas of research, this editorial seeks to promote a holistic and multidisciplinary approach to IBD treatment, combining emerging technologies, personalized medicine, and conventional therapies to improve patient outcomes.


Asunto(s)
COVID-19 , Enfermedades Inflamatorias del Intestino , Telemedicina , Humanos , Enfermedades Inflamatorias del Intestino/terapia , COVID-19/complicaciones , COVID-19/virología , COVID-19/epidemiología , Telemedicina/tendencias , Medicina de Precisión/métodos , Gastroenterología/métodos , Medicina Integrativa/métodos , Descubrimiento de Drogas
20.
ACS Infect Dis ; 10(12): 4194-4207, 2024 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-39530678

RESUMEN

Worldwide, bacterial antibiotic resistance continues to outpace the level of drug development. One way to counteract this threat to society is to identify novel ways to rapidly screen and identify drug candidates in living cells. Developing fluorescent antibiotics that can enter microorganisms and be displaced by potential antimicrobial compounds is an important but challenging endeavor due to the difficulty in entering bacterial cells. We developed a cell-based assay using a fluorescent aminoglycoside molecule that allows for the rapid and direct characterization of aminoglycoside binding in a population of bacterial cells. The assay involves the accumulation and competitive displacement of a fluorescent aminoglycoside binding probe in Escherichia coli as a Gram-negative bacterial model. The assay was optimized for high signal-to-background ratios, ease of performance for reliable outcomes, and amenability to high-throughput screening. We demonstrate that the fluorescent binding probe shows a decrease in fluorescence with cellular uptake, consistent with RNA binding, and also shows a subsequent increase upon the addition of the positive control neomycin. Fluorescence intensity increase with aminoglycosides was indicative of their relative binding affinities for A-site rRNA, with neomycin having the highest affinity, followed by paromomycin, tobramycin, sisomicin, and netilmicin. Intermediate fluorescence was found with plazomicin, neamine, apramycin, ribostamicin, gentamicin, and amikacin. Weak fluorescence was observed with kanamycin, hygromycin, streptomycin, and spectinomycin. A high degree of sensitivity was observed with aminoglycosides known to be strong binders for the 16S rRNA A-site compared with antibiotics that target other biosynthetic pathways. The quality of the optimized assay was excellent for planktonic cells, with an average Z' factor value of 0.80. In contrast to planktonic cells, established biofilms yielded an average Z' factor of 0.61. The high sensitivity of this cell-based assay in a physiological context demonstrates significant potential for identifying potent new ribosomal binding antibiotics.


Asunto(s)
Aminoglicósidos , Antibacterianos , Descubrimiento de Drogas , Escherichia coli , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Antibacterianos/farmacología , Aminoglicósidos/farmacología , Aminoglicósidos/química , Descubrimiento de Drogas/métodos , ARN Ribosómico/genética , Colorantes Fluorescentes/química , Evaluación Preclínica de Medicamentos/métodos , Pruebas de Sensibilidad Microbiana , Ensayos Analíticos de Alto Rendimiento/métodos
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