Exploration of drug science最新文献

Combating antibiotic resistance: mechanisms, challenges, and innovative approaches in antibacterial drug development 抗抗生素耐药性：机制、挑战和抗菌药物开发的创新方法

Exploration of drug science Pub Date : 2025-01-26 DOI: 10.37349/eds.2025.100887

Aiswarya Rajesh, Shraddha Subhash Pawar, Kruthi Doriya, Rambabu Dandela

{"title":"Combating antibiotic resistance: mechanisms, challenges, and innovative approaches in antibacterial drug development","authors":"Aiswarya Rajesh, Shraddha Subhash Pawar, Kruthi Doriya, Rambabu Dandela","doi":"10.37349/eds.2025.100887","DOIUrl":"https://doi.org/10.37349/eds.2025.100887","url":null,"abstract":"Antibiotic resistance is a significant threat to public health and drug development, driven largely by the overuse and misuse of antibiotics in medical and agricultural settings. As bacteria adapt to evade current drugs, managing bacterial infections has become increasingly challenging, leading to prolonged illnesses, higher healthcare costs, and increased mortality. This review explores the critical role of antibiotics in fighting infections and the mechanisms that enable bacteria to resist them. Key antibiotics discussed include carvacrol, dalbavancin, quinolones, fluoroquinolones, and zoliflodacin, each with unique actions against bacterial pathogens. Bacteria have evolved complex resistance strategies, such as enzyme production to neutralize drugs, modifying drug targets, and using efflux pumps to remove antibiotics, significantly reducing drug efficacy. Additionally, the review examines the challenges in antibiotic development, including a declining discovery rate of novel drugs due to high costs and regulatory complexities. Innovative approaches, such as structure-based drug design, combination therapies, and new delivery systems, are highlighted for their potential to create compounds with enhanced action against resistant strains. This review provides valuable insights for researchers and developers aiming to combat antibiotic resistance and advance the development of robust antibacterial therapies for future health security.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.explorationpub.com/uploads/Article/A100887/100887.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147892319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Experimental and clinical tests of FDA-approved kinase inhibitors for the treatment of neurological disorders (update 2024). fda批准的用于治疗神经疾病的激酶抑制剂的实验和临床试验（更新2024年）。

Exploration of drug science Pub Date : 2025-01-01 Epub Date: 2025-07-01 DOI: 10.37349/eds.2025.1008116

Hassan Aliashrafzadeh, Dewey Liu, Samantha De Alba, Imad Akbar, Austin Lui, Jordan Vanleuven, Ryan Martin, Zhang Wang, Da Zhi Liu

{"title":"Experimental and clinical tests of FDA-approved kinase inhibitors for the treatment of neurological disorders (update 2024).","authors":"Hassan Aliashrafzadeh, Dewey Liu, Samantha De Alba, Imad Akbar, Austin Lui, Jordan Vanleuven, Ryan Martin, Zhang Wang, Da Zhi Liu","doi":"10.37349/eds.2025.1008116","DOIUrl":"10.37349/eds.2025.1008116","url":null,"abstract":"Since our previous summary of the 74 FDA-approved kinase inhibitors in clinical and preclinical trials for non-cancerous neurological treatment, the US FDA has approved 13 additional kinase inhibitors since early 2022. This update incorporates new evidence for the now 87 FDA-approved kinase inhibitors in clinical and preclinical trials for the treatment of non-cancerous neurological disorders. By the end of October 2024, nearly all 87 FDA-approved kinase inhibitors have been tested in various animal models of non-cancerous neurological disorders, with twenty entered into clinical trials and six used for off-label treatments of neurological conditions in humans. Considering the challenges posed by intellectual property (IP), legal considerations, and limited blood-brain barrier (BBB) permeability, which may restrict some FDA-approved kinase inhibitors from effectively targeting the central nervous system (CNS), we further discuss the feasibility of designing novel proprietary analogs with enhanced BBB penetration to improve their therapeutic potential in neurological disorders. The new drugs typically retain full IP rights and remain costly; while repurposing kinase inhibitors may provide effective and affordable treatments for non-cancerous neurological disorders.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of the crosstalk between the PTEN and PAFR as well as PAFR and EGFR pathways in cancer. PTEN和PAFR之间的串扰以及PAFR和EGFR通路在癌症中的影响。

Exploration of drug science Pub Date : 2025-01-01 Epub Date: 2025-01-14 DOI: 10.37349/eds.2025.100883

Anita Thyagarajan, Zaid Sirhan, Ravi P Sahu

{"title":"Impact of the crosstalk between the PTEN and PAFR as well as PAFR and EGFR pathways in cancer.","authors":"Anita Thyagarajan, Zaid Sirhan, Ravi P Sahu","doi":"10.37349/eds.2025.100883","DOIUrl":"10.37349/eds.2025.100883","url":null,"abstract":"The integration between the tumor-suppressive and oncogenic signaling pathways controls various cellular activities of cancer cells, including cell growth and apoptosis. While the activation of oncogenes fuels cancer progression and escape mechanisms, tumor suppressors regulate and counterbalance the negative effects of oncogenic signaling. Notably, phosphatase and tensin homolog (PTEN) constitute one of the important family members of tumor suppressor genes, which play critical roles in regulating the activities of tumor cells. Thus, an impaired, mutated, or loss of PTEN is associated with low survival or high tumor recurrence rates in cancer patients. Importantly, high tumor expression of a G-protein coupled platelet-activating factor-receptor (PAFR) is associated with increased tumor progression as well as decreased overall survival and poor prognosis in malignancies such as non-small cell lung cancer (NSCLC). Along similar lines, overactivation or mutations in epidermal growth factor receptor (EGFR) signaling are detected in various human malignancies and associated with poor prognosis. The goal of the current minireview was to highlight the significance of the mechanistic insights between the PTEN and PAFR as well as the PAFR and EGFR pathways in impacting cancer growth and/or efficacy of therapeutic agents in experimental model systems.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

FDA-approved kinase inhibitors: a promising therapeutic avenue for traumatic brain injury fda批准的激酶抑制剂：创伤性脑损伤的有希望的治疗途径

Exploration of drug science Pub Date : 2024-12-02 DOI: 10.37349/eds.2024.00077

Dezhu Gao, Yu Shi, Zhiliang Wang, Weiming Liu

引用次数: 1

Bicyclic peptide-enhanced covalent inhibitor of SARS-CoV-2 3CL protease 双环肽增强SARS-CoV-2 3CL蛋白酶共价抑制剂

Exploration of drug science Pub Date : 2024-10-17 DOI: 10.37349/eds.2024.00071

Qian Wang, Yanhui Wang, Jian Li, Hong Liu, Shiyu Chen

{"title":"Bicyclic peptide-enhanced covalent inhibitor of SARS-CoV-2 3CL protease","authors":"Qian Wang, Yanhui Wang, Jian Li, Hong Liu, Shiyu Chen","doi":"10.37349/eds.2024.00071","DOIUrl":"https://doi.org/10.37349/eds.2024.00071","url":null,"abstract":"Aim: Develop technology to apply bicyclic peptides for discovering covalent inhibitors of proteases and use this technology to create bicyclic peptide—warhead conjugates for targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like (3CL) protease. Enhance the potency of the discovered bicyclic peptides for potential development into anti-SARS-CoV-2 drugs. Methods: Rational design was employed to discover the initial bicyclic peptide—warhead conjugates. Medicinal chemistry optimization was conducted to improve the potency of these peptides. Enzymatic assays and mass spectrometry characterization were performed to validate the covalent inhibition of the target protease. Results: The need for peptide display selection in discovering hit bicyclic peptides was overcome. Active bicyclic peptide—vinyl sulfone inhibitors with nanomolar potency were discovered. Optimization through medicinal chemistry strategies not only improved the potency of the peptides but also revealed residue preferences at individual positions of the bicyclic peptide inhibitors. The most potent bicyclic peptide can inhibit the target with a half-maximal inhibitory concentration (IC50) of 40.46 ± 6.35 nM. Mass spectrometry tests confirmed the covalent inhibition of the target protease by the developed peptides. Conclusions: Bicyclic peptide and vinyl sulfone conjugates are a form of covalent and potent inhibitors for targeting proteases. The rational design of bicyclic peptide ligands is feasible when structural and amino acid preference information is available. Structural information is also crucial for optimizing the potency of bicyclic peptide ligands.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"2 6","pages":"719-733"},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.explorationpub.com/uploads/Article/A100871/100871.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147886879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Enhanced breast cancer cell targeting: RGD integrin ligand potentiates RWQWRWQWR’s cytotoxicity and inhibits migration 增强乳腺癌细胞靶向性：RGD 整合素配体可增强 RWQWRWQWR 的细胞毒性并抑制迁移

Exploration of drug science Pub Date : 2024-07-19 DOI: 10.37349/eds.2024.00052

A. Barragán-Cárdenas, Daniel Castellar-Almonacid, Yerly Vargas-Casanova, C. Parra-Giraldo, Adriana Umaña-Pérez, J. López-Meza, Z. Rivera-Monroy, J. García-Castañeda

{"title":"Enhanced breast cancer cell targeting: RGD integrin ligand potentiates RWQWRWQWR’s cytotoxicity and inhibits migration","authors":"A. Barragán-Cárdenas, Daniel Castellar-Almonacid, Yerly Vargas-Casanova, C. Parra-Giraldo, Adriana Umaña-Pérez, J. López-Meza, Z. Rivera-Monroy, J. García-Castañeda","doi":"10.37349/eds.2024.00052","DOIUrl":"https://doi.org/10.37349/eds.2024.00052","url":null,"abstract":"Aim: Evaluate the selective cytotoxic effect of the palindromic sequence RWQWRWQWR and its analogues obtained by replacement of L-amino acids by D-amino acids or the functionalization by adding the RGD (integrin ligand motif) to the peptide. Methods: Peptides were obtained by SPPS, characterized by RP-HPLC and ESI-QTOF and its biological activity was evaluated using MTT assays. Evaluation of mechanism associated to the cytotoxic effect were carried out by flow cytometry, RT-qPCR, wound healing, transwell and zymography. Results: The peptides with replacements of D-amino acid showed a lesser cytotoxic effect against breast cancer cell lines, regardless it was one or several residues modified which suggested a possible specific interaction between the peptide and the cancer cell membrane besides its initial electrostatically contact. On the other hand, addition of the RGD sequence to the palindromic peptide in the N-terminal end resulted in a greater cytotoxic effect against cell lines derived from the three mainly diagnosed breast cancer molecular subtypes. An approximation on mechanisms associated to this effect was evaluated on MCF-7 cells, it shows that the peptide induced apoptosis by activating intrinsic and extrinsic pathway, which correlates with the possibility of a specific interaction, and induces mitochondrial depolarization with release of oxygen reactive species. Also, this peptide induces a reduction in migration and invasion associated with a diminish in metalloprotease 9 activity and a lesser release of IL-6, IL-10 and arginase cytokines. Conclusions: Our results suggest that this promising peptide can be considered for preclinical evaluation in the development of drugs to treat breast cancer and thus mitigate the impact of this disease.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":" 365","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141823599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Plants and fungi metabolites as novel autophagy inducers and senescence inhibitors 作为新型自噬诱导剂和衰老抑制剂的植物和真菌代谢物

Exploration of drug science Pub Date : 2024-07-01 DOI: 10.37349/eds.2024.00051

Rivka Ofir

{"title":"Plants and fungi metabolites as novel autophagy inducers and senescence inhibitors","authors":"Rivka Ofir","doi":"10.37349/eds.2024.00051","DOIUrl":"https://doi.org/10.37349/eds.2024.00051","url":null,"abstract":"Premature aging can be partially explained by inefficient autophagy (the process of cellular self-digestion that recycles intracellular components) and premature senescence (cease of cellular division without cell death activation). Autophagy and senescence are among the basic biochemical pathways in plants and fungi suggesting that some of their metabolites have the potential to act as autophagy inducers (AI) and senescence inhibitors (SI) and to inhibit inflammation and human aging. Several compounds have already been identified: trehalose and resveratrol are natural compounds that act as AI; flavonoids found in fruit and vegetables (curcumin, quercetin, and fisetin) are among the first SI discovered so far. New AI/SI can be identified using various approaches like hypothesis-driven approach for screening receptor agonists using an in-silico library of thousands of natural compounds; cheminformatics studies of phytochemicals using docking and molecular dynamics simulation, structure similarities/mimicry in vitro, “blind” high throughput screening (HTS) of libraries of natural metabolites against relevant models, and more. This article aims to promote the use of plant and fungi novel resources to identify bioactive molecules relevant for healthy aging based on the knowledge that plants and fungi use autophagy and senescence mechanisms for their own survival and homeostasis. As autophagy and senescence are interconnected, how drugs targeting autophagy, senescence, or both could contribute to healthy aging in humans will be speculated.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"10 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141703566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study 去甲苏氨酸类单体生物碱和二聚生物碱与α-微管蛋白的相互作用：分子对接研究

Exploration of drug science Pub Date : 2024-05-21 DOI: 10.37349/eds.2024.00047

Gérard Vergoten, Christian Bailly

{"title":"Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study","authors":"Gérard Vergoten, Christian Bailly","doi":"10.37349/eds.2024.00047","DOIUrl":"https://doi.org/10.37349/eds.2024.00047","url":null,"abstract":"Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"131 38","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141115055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Pain management for the neurosurgical patient in spinal procedures: overview of historic and new modalities 脊柱手术中神经外科患者的疼痛管理：历史和新模式概述

Exploration of drug science Pub Date : 2024-05-21 DOI: 10.37349/eds.2024.00046

Ashley M. Carter, Samantha Yost, Jessica Tobin, Simran Phuyal, Brandon Lucke-Wold

引用次数: 0

Stryphnodendron adstringens have a modulatory effect on inflammatory cytokines markers of in vitro activated macrophages Stryphnodendron adstringens 对体外活化巨噬细胞的炎症细胞因子标记有调节作用

Exploration of drug science Pub Date : 2024-05-11 DOI: 10.37349/eds.2024.00045

I. D. da Cruz, C. F. Teixeira, N. L. Pellenz, M. Mastella, V. Azzolin, Euler Esteves Ribeiro, F. Barbisan

{"title":"Stryphnodendron adstringens have a modulatory effect on inflammatory cytokines markers of in vitro activated macrophages","authors":"I. D. da Cruz, C. F. Teixeira, N. L. Pellenz, M. Mastella, V. Azzolin, Euler Esteves Ribeiro, F. Barbisan","doi":"10.37349/eds.2024.00045","DOIUrl":"https://doi.org/10.37349/eds.2024.00045","url":null,"abstract":"Aim: The purpose of this study is to conduct a comprehensive investigation into the modulatory effects of Stryphnodendron adstringens (Mart.; S. adstringens), a Brazilian wound-healing plant, on the expression of inflammatory cytokines. This will be achieved using an in vitro protocol with the commercial macrophage cell line RAW 264.7. Methods: The macrophage inflammatory response was induced by the natural antigen phytohemagglutinin (PHA), with and without supplementation of different concentrations of S. adstringens extract. The effects on cell proliferation rate and the concentration and production of transcripts of pro-inflammatory cytokines interleukin 1β (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), as well as the anti-inflammatory cytokine IL-10, were assessed using spectrophotometric, immunoassay, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) techniques. Results: S. adstringens extract at all concentrations tested here reduced the cellular proliferation rate of activated macrophages. Extracts at concentrations of 0.49 mg/mL and 0.99 mg/mL decreased the protein and gene expression of pro-inflammatory cytokines, exhibiting the opposite effect concerning IL-10. Conclusions: The findings suggest that the wound-healing action of S. adstringens may encompass differential modulation of inflammation associated with tissue injury.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"117 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140987797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0