Current medicinal chemistry最新文献

{"title":"TLR2 Activation as a Marker of Severe COVID-19 and a Potential Therapeutic Target.","authors":"Xianxian Mao, Yijia Wu, Xinyi Zhang, Tian Zhou, Houda Huang, Mingui Fu, Yisong Qian","doi":"10.2174/0109298673327301241016063917","DOIUrl":"https://doi.org/10.2174/0109298673327301241016063917","url":null,"abstract":"<p><p>SARS-CoV-2-induced COVID-19 has been a serious public health problem, resulting in millions of lives lost over the previous three years. Although the direct infection caused by virus invasion is important for the pathobiology of COVID-19, the hyperinflammatory response and tissue injury are major contributors in critically ill patients. As a host sensor, toll-like receptor 2 (TLR2) recognizes multiple pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), producing various inflammatory cytokines and inflammatory cell death signals, which are central to the inflammatory pathology observed in COVID-19. The objectives of this narrative review are to summarize the role of TLR2 activation during SARS-CoV-2 infection and emphasize the importance of SARS-CoV-2 viral proteins in TLR2 activation. Additionally, we presented some compounds related to TLR2 regulation clinically or experimentally, which may provide new insights into targets for pharmaceutical discovery and development.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide Association Studies of Diabetic Kidney Disease in East Asians With Type 2 Diabetes: Achievements and Future Perspectives.","authors":"Binura Taurbekova, Kymbat Mukhtarova, Zhandos Salpynov, Joseph Almazan, Kuralay Atageldiyeva, Antonio Sarria-Santamera","doi":"10.2174/0109298673328801241015165257","DOIUrl":"https://doi.org/10.2174/0109298673328801241015165257","url":null,"abstract":"<p><p>Diabetic kidney disease is a devastating diabetic complication, affecting up to half of people suffering from diabetes. The global burden of diabetic kidney disease is steadily increasing worldwide along with the growing prevalence of type 2 diabetes. The epidemic rise of type 2 diabetes is primarily observed in Asia, including the East Asian regions. It is generally accepted that heredity is one of the main determinants in the pathogenesis of diabetic kidney disease. Since the advent of genome-wide association studies, numerous studies have been published to identify the genetic loci susceptible to diabetic kidney disease among diverse populations. Although genome-wide association studies exploring diabetic kidney disease susceptibility loci have focused primarily on populations of European descent, a number of novel genetic variants associated with diabetic kidney disease have also been successfully revealed among East Asians. A comprehensive analysis of the genetic architecture and pathophysiological pathways of diabetic kidney disease may allow the identification of new potential therapeutic targets. This review aimed to summarize genome-wide association studies examining genetic variants associated with diabetic kidney disease in the populations of East Asian ancestry with type 2 diabetes and presented our perspective on the future of this field.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing Generalizable Scoring Functions for Molecular Docking: Challenges and Perspectives.","authors":"Rodrigo Quiroga, Marcos Villarreal","doi":"10.2174/0109298673334469241017053508","DOIUrl":"https://doi.org/10.2174/0109298673334469241017053508","url":null,"abstract":"<p><p>Structure-based drug discovery methods, such as molecular docking and virtual screening, have become invaluable tools in developing novel drugs. At the core of these methods are Scoring Functions (SFs), which predict the binding affinity between ligands and protein targets. This study aims to review and contextualize the challenges and best practices in training novel scoring functions to improve their accuracy and generalizability in predicting protein-ligand binding affinities. Effective training of scoring functions requires careful attention to the quality of training data and methodologies. We emphasize the need for robust training strategies to produce consistent and generalizable SFs. Key considerations include addressing hidden biases and overfitting in machine-learning models, as well as ensuring the use of high-quality, unbiased datasets for both training and evaluation of SFs. Innovative hybrid methods, combining the advantages of empirical and machine-learning approaches, hold promise for outperforming current scoring functions while displaying greater generalizability and versatility.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fustin, a Potent Phytochemical, Attenuates Scopolamine-induced Memory Impairment and Neurodegeneration by Modulating Neuroinflammation and Neurotransmitters.","authors":"Ebtihaj J Jambi, Muhammad Afzal, Fahad A Al-Abbasi, Ehssan Moglad, Salwa D Al-Qahtani, Naif A R Almalki, Sami I Alzarea, Faisal Imam, Nadeem Sayyed, Imran Kazmi","doi":"10.2174/0109298673330002241015085330","DOIUrl":"https://doi.org/10.2174/0109298673330002241015085330","url":null,"abstract":"<p><strong>Introduction: </strong>Fustin, a photogenic flavanol found in the plant Rhus verniciflua Stokes, has been involved in multiple disease ailments and has a beneficial pharmacological effect and a history of use in traditional medicine. The present research aimed to study the impact of fustin on scopolamine (SCOP)-induced memory impairment and neurodegeneration by modulating neuroinflammation and neurotransmitters in rats.</p><p><strong>Methods: </strong>A total of 30 healthy Wistar rats were allocated into five groups (n=6). Group I- served as control and received saline solution (1mL/kg i.p.), group -II- fustin (100 mg/kg, orally), group -III -SCOP (1 mg/kg, i.p.), and group -IV and V were given fustin (50 and 100 mg/kg/p.o.) with SCOP (1 mg/kg, i.p.) for 14-days. After 14 days, 2 hours after SCOP injection, the Y-maze and Morris water maze (MWM) tests were performed. After behavioral tests rats were subsequently euthanized, and brain supernatants were used to estimate choline-acetyltransferase (ChAT), acetylcholinesterase (AChE), antioxidant [superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)], and total protein, oxidative stress markers [nitrate and malondialdehyde (MDA)], pro-inflammatory markers [tumor necrosis factor (TNF-α), and Interleukins-1β (IL-1β) and IL-6]. Also, neurotransmitters such as serotonin (5-HT), dopamine (DA), ϒ-amino butyric acid (GABA), acetylcholine (Ach), and noradrenaline (NA) contents were performed.</p><p><strong>Results: </strong>Fustin exhibited substantial behavioral improvement in the Y-maze measures spontaneous alterations percentage (SA%) and decreased latency time following the acquisition and prolonged time spent in the probe trial in the MWM test. Moreover, fustin inhibits enhanced neuroinflammatory cytokines and oxidative stress markers and improves the neurotransmitters.</p><p><strong>Conclusion: </strong>The findings of this study suggest that fustin inhibits SCOP impact on cognitive abilities in rats. The present investigation demonstrates that fustin, a potent phytochemical, effectively mitigated the behavioral and physiological changes induced by SCOP in rats. This was primarily achieved by modulating the levels of inflammatory response and neurotransmitters.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Inflammatory Biomarkers in the Pre-Biopsy Risk Stratification of Patients with Suspicious Mri Lesions of the Prostate: Where Should We Head?","authors":"Ilias Giannakodimos, Napoleon Moulavasilis, Konstantinos Stravodimos, Evaggelos Fragkiadis","doi":"10.2174/0109298673344979241014114336","DOIUrl":"https://doi.org/10.2174/0109298673344979241014114336","url":null,"abstract":"","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary on the Obtention of Semi-Synthetic Derivatives from Natural Products for Medicinal Applications: Advances, Challenges, and Perspectives.","authors":"Musso Florencia, Biscussi Brunella","doi":"10.2174/0109298673336208241014102943","DOIUrl":"https://doi.org/10.2174/0109298673336208241014102943","url":null,"abstract":"<p><p>Plants have historically been a primary source of medicines due to their diverse molecular and structural composition. Plant metabolism, comprising primary and secondary processes, produces primary metabolites crucial for growth and secondary metabolites, or natural products (NPs), with specific biological functions. These small molecules are instrumental in pharmacology for their ability to penetrate biological barriers and interact with intracellular targets. The structural complexity and limited availability of NPs have led to research focusing on enhancing their diversity through semi-synthesis. In this commentary, examples of various semisynthetic derivatives of NPs obtained through different synthetic strategies, such as organic semi-synthesis or combinatorial chemistry, are cited. Additionally, the importance of developing hybrid molecules based on the combination of two or more distinct pharmacophores is emphasized. This strategy has been widely implemented to obtain new multitarget drugs applicable to the treatment of multifactorial neurodegenerative diseases, where stimulating the cholinergic system by modulating different therapeutic targets is crucial. However, challenges, such as structural complexity, raw material availability, and the need for precise synthetic methods, persist. Innovations in synthetic routes, sustainable harvesting, and biotechnological advances are critical to overcoming these barriers. The integration of omics technologies, green chemistry principles, and global collaboration is essential to maximize the potential of NPs in drug development, ensuring sustainable and efficient production of new therapeutics.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism Exploration of Astaxanthin in the Treatment of Adriamycin-induced Cardiotoxicity Based on Network Pharmacology and Experimental Validation.","authors":"Yu Zhu, Mengyao Chen, Lin Xie, Yijun Pan, Yuntian Yang, Guoxing Wan","doi":"10.2174/0109298673329567241014071914","DOIUrl":"https://doi.org/10.2174/0109298673329567241014071914","url":null,"abstract":"<p><strong>Introduction: </strong>Astaxanthin (AXT), a natural antioxidant recognized for its therapeutic potential in cancer and cardiovascular diseases, holds promise in mitigating adriamycin-induced cardiotoxicity (AIC). Nevertheless, the underlying mechanisms of AXT in AIC mitigation remain to be elucidated. Consequently, this study endeavors to elucidate the mechanism of AXT against AIC, employing an integrated approach.</p><p><strong>Methods: </strong>Network pharmacology, molecular docking, and molecular dynamics simulations were harnessed to explore the molecular mechanism underlying AXT's action against AIC. Furthermore, the in-vitro AIC model was established with the H9c2 cell to generate transcriptome data for validation.</p><p><strong>Results: </strong>A total of 533 putative AXT targets and 1478 AIC-related genes were initially screened by database retrieval and bioinformatics analysis. A total of 248 potential targets of AXT against AIC and several signaling pathways were identified by network pharmacology and enrichment analysis. Two core genes (CCL2 and NOS3) and the AGE-RAGE signaling pathway in diabetic complications were further highlighted by transcriptome validation based on the AIC in-vitro model. Additionally, molecular docking and dynamics analyses supported the robust binding affinity of AXT with the core targets.</p><p><strong>Conclusion: </strong>The study suggested that AXT might ameliorate AIC through the inhibition of CCL2 and NOS3 as well as AGE-RAGE signaling, which provide a theoretical basis for the development of a strategy against AIC.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hybrid/Chimera Drugs - Part 1 - Drug Hybrids Affecting Diseases of the Central Nervous System.","authors":"Abraham Nudelman","doi":"10.2174/0109298673305662240702071354","DOIUrl":"https://doi.org/10.2174/0109298673305662240702071354","url":null,"abstract":"<p><p>This review, focused on hybrid drugs, is the third in a series of reviews, where the first two reviews dealt with a) dimeric drugs, b) mutual prodrugs - codrugs. The compounds designated as hybrids are comprised of two (and sometimes three) biologically active entities, linked by metabolically stable bridges. In some cases, one of the two components of the hybrids serves as a carrier for the second component, and most frequently, the components elicit their individual biological properties, which are commonly synergistic or complementary. Due to the very large number of publications dealing with hybrid drugs, the present review is restricted to hybrids acting in the central nervous system. Future reviews will cover fields such as antimicrobial, anticancer, and antiviral hybrids, and cardiovascular active hybrids. The selected articles reviewed herein were published between the years 2000-2022 with partial coverage of the year 2023.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning-based Macrophage Signature for Predicting Prognosis and Immunotherapy Benefits in Cholangiocarcinoma.","authors":"Junkai Huang, Yu Chen, Zhiguo Tan, Yinghui Song, Kang Chen, Sulai Liu, Chuang Peng, Xu Chen","doi":"10.2174/0109298673342462241010072026","DOIUrl":"https://doi.org/10.2174/0109298673342462241010072026","url":null,"abstract":"<p><strong>Aims: </strong>We aimed to develop a macrophage signature for predicting clinical outcomes and immunotherapy benefits in cholangiocarcinoma.</p><p><strong>Background: </strong>Macrophages are potent immune effector cells that can change phenotype in different environments to exert anti-tumor and anti-tumor functions. The role of macrophages in the prognosis and therapy benefits of cholangiocarcinoma was not fully clarified.</p><p><strong>Objective: </strong>The objective of this study is to develop a prognostic model for cholangiocarcinoma.</p><p><strong>Methods: </strong>The macrophage-related signature (MRS) was developed using 10 machine learning methods with TCGA, GSE89748 and GSE107943 datasets. Several indicators (TIDE score, TMB score and MATH score) and two immunotherapy datasets (IMvigor210 and GSE91061) were used to investigate the performance of MRS in predicting the benefits of immunotherapy.</p><p><strong>Results: </strong>The Lasso + CoxBoost method's MRS was considered a robust and stable model that demonstrated good accuracy in predicting the clinical outcome of patients with cholangiocarcinoma; the AUC of the 2-, 3-, and 4-year ROC curves in the TCGA dataset were 0.965, 0.957, and 1.000. Moreover, MRS acted as an independent risk factor for the clinical outcome of cholangiocarcinoma cases. Cholangiocarcinoma cases with higher MRS scores are correlated with a higher TIDE score, higher tumor escape score, higher MATH score, and lower TMB score. Further analysis suggested high MRS score indicated a higher gene set score correlated with cancer-related hallmarks.</p><p><strong>Conclusion: </strong>With regard to cholangiocarcinoma, the current study created a machine learning-based MRS that served as an indication for forecasting the prognosis and therapeutic advantages of individual cases.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, Molecular Docking, Pharmacokinetic Properties, and Molecular Dynamics Simulation of Sulfonyl Derivatives of Benzimidazole against Parkinson's Disease.","authors":"Subarna Roy, Subhankar Basak, Shristi Roy, Paromita Dey, Hema Barman, Bhagat Singh, Kaushik Sarkar, Subhadeep Sen, Rajesh Kumar Das, Sudhan Debnath, Goutam Biswas","doi":"10.2174/0109298673337912241007120510","DOIUrl":"https://doi.org/10.2174/0109298673337912241007120510","url":null,"abstract":"<p><strong>Introduction: </strong>The disability and mortality related to Parkinson's disease (PD), a neurodegenerative disease, are increasing globally at a faster rate than other neurological disorders. With no permanent cure for PD, there is an urgent need to develop novel and effective anti-PD drugs.</p><p><strong>Method: </strong>Targeting monoamine oxidases (MAO), which catalyze the breakdown of neurotransmitters, is one way to treat neurodegenerative diseases. In this context, an initial molecular docking of twenty designed sulfonyl derivatives of benzimidazole against monoamine oxidase B (MAO-B) associated with PD was conducted using AutoDock Vina.</p><p><strong>Result: </strong>The results were compared with those of the conventional inhibitors, selegiline and rasagiline. Based on the docking score, the in-silico pharmacokinetic properties (ADME), drug-likeness, and toxicity profiles of the newly synthesized molecules were examined using SwissADME, PreADMET, ProTox-3.0, vNN, and ADMETlab web tools. Then, twelve potential derivatives were synthesized and characterized by IR, 1H-NMR, 13C-NMR, 19F-NMR (for some compounds), and mass spectrometry. Derivatives 2cj and 1bj were the two molecules having the best binding affinity of -11.9 and -11.8 kcal/mol, respectively, against MAOB, exhibiting a higher binding affinity compared to that of some commercially available drugs. A 50 ns MD simulation run was performed to observe the stability of the top two docked complexes, MAO-B-2cj and MAO-B-1bj, in order to further validate the efficacy of those two substances. Moreover, the MM-PBSA method was used to calculate the final, binding free energy of the simulated (MAO-B-2cj) complex.</p><p><strong>Conclusion: </strong>This study indicates that the binding affinity of most of the hits was superior to that of known MAO inhibitors; therefore, these newly synthesized benzimidazole derivatives may be developed into essential drug candidates for the treatment of PD.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}