Current computer-aided drug design最新文献

{"title":"Exploring the Molecular Mechanism by which Kaempferol Attenuates Sepsis-related Acute Respiratory Distress Syndrome Based on Network Pharmacology and Experimental Verification.","authors":"Weichao Ding, Changbao Huang, Juan Chen, Wei Zhang, Mengmeng Wang, Xiaohang Ji, Shinan Nie, Zhaorui Sun","doi":"10.2174/0115734099295805240126043059","DOIUrl":"10.2174/0115734099295805240126043059","url":null,"abstract":"<p><strong>Background: </strong>Sepsis-related acute respiratory distress syndrome (ARDS) is a fatal disease without effective therapy. Kaempferol is a flavonoid compound extracted from natural plant products; it exerts numerous pharmacological effects. Kaempferol attenuates sepsis-related ARDS; however, the underlying protective mechanism has not been elucidated completely.</p><p><strong>Objectives: </strong>This study aimed to use network pharmacology and experimental verification to investigate the mechanisms by which kaempferol attenuates sepsis-related ARDS.</p><p><strong>Methods: </strong>We screened the targets of kaempferol by PharMapper, Swiss Target Prediction, and CTD database. We identified the targets of sepsis-related ARDS by GeneCards, DisGeNet, OMIM, and TTD. The Weishengxin platform was used to map the targets of both kaempferol and sepsis-related ARDS. We created a Venn diagram to identify the intersection targets. We constructed the \"component-intersection targets-disease\" network diagram using Cytoscape 3.9.1 software. The intersection targets were imported into the STRING database for developing the protein-protein interaction network. Metascape was used for the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We selected the leading 20 KEGG pathways to establish the KEGG relationship network. Finally, we performed experimental verification to confirm our prediction results.</p><p><strong>Results: </strong>Through database screening, we obtained 502, 360, and 78 kaempferol targets, disease targets of sepsis-related ARDS, and intersection targets, respectively. The core targets consisted of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, albumin (ALB), IL-1β, and AKT serine/ threonine kinase (AKT)1. GO enrichment analysis identified 426 items, which were principally involved in response to lipopolysaccharide, regulation of inflammatory response, inflammatory response, positive regulation of cell migration, positive regulation of cell adhesion, positive regulation of protein phosphorylation, response to hormone, regulation of reactive oxygen species (ROS) metabolic process, negative regulation of apoptotic signaling pathway, and response to decreased oxygen levels. KEGG enrichment analysis identified 151 pathways. After eliminating the disease and generalized pathways, we obtained the hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and phosphoinositide 3-kinase (PI3K)-Akt signaling pathways. Our experimental verification confirmed that kaempferol blocked the HIF-1, NFκκB, and PI3K-Akt signaling pathways, diminished TNF-α, IL-1β, and IL-6 expressions, suppressed ROS production, and inhibited apoptosis in lipopolysaccharide (LPS)-induced murine alveolar macrophage (MH-S) cells.</p><p><strong>Conclusion: </strong>Kaempferol can reduce inflammatory response, ROS production, and cell apoptosis by acting on the HIF-1, NF-κB, and PI3K-Akt signaling pathways, thereby all","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"166-178"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139699107","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}

{"title":"Astragaloside IV Overcomes Anlotinib Resistance in Non-small Cell Lung Cancer through miR-181a-3p/UPR-ERAD Axis.","authors":"Lihuai Wang, Tonglin Sun, Xiao Yang, Zhi Wen, Yinhui Sun, Hua Liu","doi":"10.2174/0115734099252873231117072107","DOIUrl":"10.2174/0115734099252873231117072107","url":null,"abstract":"<p><strong>Background: </strong>Astragaloside IV (AS-IV) has been shown to have a curative effect on non-small cell lung cancer (NSCLC). This study aimed to elucidate the role of AS-IV in NSCLC cell anlotinib resistance (AR).</p><p><strong>Methods: </strong>The NSCLC/AR cells, resistant to anlotinib, have been produced. The role of AS-IV in the AR of NSCLC cells about the miR-181a-3p/unfolded protein response (UPR)- endoplasmic reticulum associated degradation (ERAD) pathway was then discussed by treating the cells with anlotinib or AS-IV, or by manipulating them with inhibitors or mimics of miR- 181a-3p, HRD1 or Derlin-1 overexpression plasmids.</p><p><strong>Results: </strong>We found that AS-IV could suppress the AR of NSCLC cells. In addition, miR-181a- 3p was elevated in NSCLC/AR cells. Functionally, AS-IV limited the AR of NSCLC cells by reducing miR-181a-3p. Further, activation of the UPR-ERAD pathway was correlated with AR in NSCLC cells. Increased sensitivity of NSCLC cells to anlotinib caused by miR-181a-3p inhibitor could be reversed by overexpression of HRD1 or Derlin-1.</p><p><strong>Conclusion: </strong>This research revealed a promising NSCLC/AR treatment approach by showing that AS-IV exposed NSCLC cells to anlotinib by inhibiting the miR-181a-3p/UPR-ERAD axis.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"441-451"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139682149","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}

{"title":"Status and Prospects of Research on Deep Learning-based <i>De Novo</i> Generation of Drug Molecules.","authors":"Huanghao Shi, Zhichao Wang, Litao Zhou, Zhiwang Xu, Liangxu Xie, Ren Kong, Shan Chang","doi":"10.2174/0115734099287389240126072433","DOIUrl":"10.2174/0115734099287389240126072433","url":null,"abstract":"<p><p>Traditional molecular <i>de novo</i> generation methods, such as evolutionary algorithms, generate new molecules mainly by linking existing atomic building blocks. The challenging issues in these methods include difficulty in synthesis, failure to achieve desired properties, and structural optimization requirements. Advances in deep learning offer new ideas for rational and robust <i>de novo</i> drug design. Deep learning, a branch of machine learning, is more efficient than traditional methods for processing problems, such as speech, image, and translation. This study provides a comprehensive overview of the current state of research in <i>de novo</i> drug design based on deep learning and identifies key areas for further development. Deep learning-based <i>de novo</i> drug design is pivotal in four key dimensions. Molecular databases form the basis for model training, while effective molecular representations impact model performance. Common DL models (GANs, RNNs, VAEs, CNNs, DMs) generate drug molecules with desired properties. The evaluation metrics guide research directions by determining the quality and applicability of generated molecules. This abstract highlights the foundational aspects of DL-based <i>de novo</i> drug design, offering a concise overview of its multifaceted contributions. Consequently, deep learning in <i>de novo</i> molecule generation has attracted more attention from academics and industry. As a result, many deep learning-based <i>de novo</i> molecule generation types have been actively proposed.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"257-269"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139699108","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}

{"title":"Accelerating Rheumatoid Arthritis Drug Repurposing: A Computational Approach.","authors":"Muskan Gupta, Tuhin Mukherjee, Satyajit Mohanty","doi":"10.2174/0115734099326517240801035901","DOIUrl":"10.2174/0115734099326517240801035901","url":null,"abstract":"","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"125-128"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899212","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}

{"title":"<i>In silico</i> Study on Natural Chemical Compounds from Citric Essential Oils as Potential Inhibitors of an Omicron (BA.1) SARS-CoV-2 Mutants' Spike Glycoprotein.","authors":"Olha Ovchynnykova, Jordhan D Booth, Trey M Cocroft, Kostyantyn M Sukhyy, Karina Kapusta","doi":"10.2174/0115734099275132231213055138","DOIUrl":"10.2174/0115734099275132231213055138","url":null,"abstract":"<p><strong>Background: </strong>SARS-CoV-2's remarkable capacity for genetic mutation enables it to swiftly adapt to environmental changes, influencing critical attributes, such as antigenicity and transmissibility. Thus, multi-target inhibitors capable of effectively combating various viral mutants concurrently are of great interest. This study aimed to investigate natural compounds that could unitedly inhibit spike glycoproteins of various Omicron mutants. Implementation of various in silico approaches allows us to scan a library of compounds against a variety of mutants in order to find the ones that would inhibit the viral entry disregard of occurred mutations.</p><p><strong>Methods: </strong>An extensive analysis of relevant literature was conducted to compile a library of chemical compounds sourced from citrus essential oils. Ten homology models representing mutants of the Omicron variant were generated, including the latest 23F clade (EG.5.1), and the compound library was screened against them. Subsequently, employing comprehensive molecular docking and molecular dynamics simulations, we successfully identified promising compounds that exhibited sufficient binding efficacy towards the receptor binding domains (RBDs) of the mutant viral strains. The scoring of ligands was based on their average potency against all models generated herein, in addition to a reference Omicron RBD structure. Furthermore, the toxicity profile of the highest-scoring compounds was predicted.</p><p><strong>Results: </strong>Out of ten built homology models, seven were successfully validated and showed to be reliable for <i>in silico</i> studies. Three models of clades 22C, 22D, and 22E had major deviations in their secondary structure and needed further refinement. Notably, through a 100 nanosecond molecular dynamics simulation, terpinen-4-ol emerged as a potent inhibitor of the Omicron SARS-CoV-2 RBD from the 21K clade (BA.1); however, it did not show high stability in complexes with other mutants. This suggests the need for the utilization of a larger library of chemical compounds as potential inhibitors.</p><p><strong>Conclusion: </strong>The outcomes of this investigation hold significant potential for the utilization of a homology modeling approach for the prediction of RBD's secondary structure based on its sequence when the 3D structure of a mutated protein is not available. This opens the opportunities for further advancing the drug discovery process, offering novel avenues for the development of multifunctional, non-toxic natural medications.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"466-478"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139099417","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}

{"title":"Designing Drug Delivery Vehicles based on N-(2-Hydroxypropyl) Methacrylamide.","authors":"Ramakrishna Prasad Are, Anju R Babu","doi":"10.2174/0115734099278986231228070823","DOIUrl":"10.2174/0115734099278986231228070823","url":null,"abstract":"<p><strong>Background: </strong>The development of polymeric-based drug delivery has seen faster growth in the past two decades. In polymers, copolymers are utilized as drug carriers to decrease the side effects and dosage-related toxicity.</p><p><strong>Objectives: </strong>The primary objective of the study is to utilize computational resources to design drug molecules and perform <i>in silico</i> physicochemical property analysis. In our study, we designed new copolymers based on N-(2-Hydroxypropyl) methacrylamide as backbone along with polyethylene glycol and lauryl methacrylate.</p><p><strong>Methods: </strong>Different functional groups were selected for attaching to the side chain of the copolymers through a random trial and error approach. In order to predict the pharmacokinetic properties (absorption, distribution, metabolism, excretion, and toxicity), the designed copolymer molecules were evaluated utilizing Swiss ADME and pkCSM pharmacokinetics servers. Molecular interaction between the designed copolymer molecules and human serum albumin was performed using AutoDock Vina and PatchDock server.</p><p><strong>Results: </strong>The designed molecules are shown to be soluble in water and have high gastrointestinal absorption. Only one molecule is predicted to pass through the blood-brain barrier. Two designed molecules have been shown to have carcinogenic properties. Lethal dose 50, cytochrome P450, and permeability glycoprotein substrate formation were also analyzed for toxicity and metabolism.</p><p><strong>Conclusion: </strong>Our study will provide insight for designing new drug compounds or carriers and analyzing their physicochemical properties to further optimize compounds for clinical studies.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"302-315"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139572445","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}

{"title":"Anti-inflammatory Potential of <i>Costus speciosus</i> rhizome Bioactive Phytochemicals: A Combined GC-MS and Computational Approach Targeting TLR-4 Signaling.","authors":"Aditya Raj, Arghya Chakravorty, Sahil Luktuke, Sourav Santra, Sudip Das, Subhrajeet Sahoo, Karthikeyan Ramesh, Nidha Fathima Ali, Siva Sankar Sana, Sivaraman Jayanthi, Arabinda Samanta, Vimala Raghavan","doi":"10.2174/0115734099309926241007055607","DOIUrl":"10.2174/0115734099309926241007055607","url":null,"abstract":"<p><strong>Background: </strong>Plants represent a rich reservoir of bioactive compounds with established therapeutic value in diverse diseases. Notably, the Toll-like receptor-4 (TLR-4) signaling pathway plays a pivotal role in inflammation. Upon engagement with pro-inflammatory ligands like lipopolysaccharide, TLR-4 triggers downstream cascades involving nuclear factor ĸappa B and mitogen- activated protein kinases. This signaling cascade ultimately dictates the onset and progression of inflammatory diseases. Therefore, targeting TLR-4 signaling offers a promising therapeutic approach for managing inflammatory disorders.</p><p><strong>Methods: </strong>This study investigated the potential of <i>Costus speciosus</i> rhizome phytocompounds, a traditional medicinal plant, as novel as modulators of TLR-4 signaling, highlighting their mechanisms of action and potential clinical applications. In the present study, 18 phytocompounds isolated from the rhizome of <i>Costus speciosus</i>, were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach.</p><p><strong>Results: </strong>The compounds exhibited binding affinities ranging from -4.087 to -8.93 kcal/mol with the TLR-4 protein due to the formation of multiple intermolecular interactions. Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, methyl ester (compound 7) exhibited exceptional binding energy (-8.93 kcal/mol), indicating strong affinity for the TLR-4 protein. Additionally, compound 7 displayed favorable ADMET properties, suggesting promising drug development potential. Molecular dynamics simulations confirmed the stability of the compound 7-TLR4 complex, further supporting its ability to modulate TLR-4 signaling.</p><p><strong>Conclusion: </strong>These findings highlight the therapeutic potential of <i>Costus speciosus</i> phytocompounds, particularly compound 7, as potent anti-inflammatory modulators. Further research is warranted to validate their anti-inflammatory and neuroprotective effects in pre-clinical models, paving the way for their development as novel therapeutic agents for inflammatory diseases.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"285-301"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483985","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}

{"title":"Computational Exploration of Isatin Derivatives for InhA Inhibition in Tuberculosis: Molecular Docking, MD Simulations and ADMET Insights.","authors":"Vaishali Pavalbhai Patel, Rati Kailash Prasad Tripathi, Abhay Dharamsi","doi":"10.2174/0115734099333313240909103833","DOIUrl":"10.2174/0115734099333313240909103833","url":null,"abstract":"<p><strong>Background: </strong>Anti-tubercular drug discovery is a critical research area aimed at addressing the global health burden imposed by <i>Mycobacterium tuberculosis</i>. Nowadays, computational techniques have increased the likelihood of drug development compared to traditional, labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their diverse pharmacological activities.</p><p><strong>Objective: </strong>To identify novel isatin derivatives that could serve as potential chemical templates for anti-TB drug discovery by targeting InhA.</p><p><strong>Methods: </strong>The present work utilized various computational approaches, including molecular docking, binding free energy calculations, and conformational alignment studies to investigate the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within InhA active site. Study also employed MD simulations of the most promising molecule to check the stability of the protein-ligand complex and <i>in-silico</i> ADMET profiling of the top compounds to predict their pharmacokinetic and toxicity properties.</p><p><strong>Results: </strong>Results provided insights into the structural features contributing to InhA inhibition, assessing overall drug-like characteristics of isatin derivatives and identified compound 48 (BA= -10.4 kcal mol^-1) with potential for further optimization. MD simulation analysis revealed that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational fluctuations and enhanced stability.</p><p><strong>Conclusion: </strong>Considering the aforementioned, isatin derivatives represents a novel framework for creating targeted InhA inhibitors during anti-<i>TB</i> therapy. However, experimental validations and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential InhA inhibitors for TB treatment.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"226-254"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142304518","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}

{"title":"Mechanisms Underlying the Attenuating Effects of Bugantang on Liver Fibrosis based on Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation.","authors":"Taojing Zhang, Jia Chang, Zengle Zheng, Guobi Chen, Yiping Wu, Jinxiang Xiang, Jing Chen","doi":"10.2174/0115734099335133241030110644","DOIUrl":"https://doi.org/10.2174/0115734099335133241030110644","url":null,"abstract":"<p><strong>Background: </strong>Liver fibrosis, a chronic liver disease, threatens people's health, increases the burden of healthcare, and currently lacks effective treatment measures. Bugantang (BGT) is a traditional Chinese herbal prescription from Jin Kui Yi with promising potential for treating liver fibrosis. Despite this potential, the efficacy and mechanism for treating liver fibrosis remain unclear.</p><p><strong>Objective: </strong>To primarily prove the efficacy, predict the active components of BGT, and explore the mechanism of BGT on liver fibrosis.</p><p><strong>Methods: </strong>The liver condition of CCL4-induced mice was examined using hematoxylin and eosin staining. The targets and active compounds of BGT were sourced from HERB and TCMSP databases, while the targets related to liver fibrosis were acquired from DisGeNET, Gene Expression Omnibus, and GeneCards databases. The core targets were identified, and the network of protein-protein interactions was established. KEGG and GO analyses were performed on DAVID. Molecular docking and molecular dynamics simulations assessed the active components' interactions with potential targets.</p><p><strong>Results: </strong>A total of 215 targets and 152 active compounds were identified for BGT. The network analysis identified kaempferol, quercetin, 2-(2,4-dihydroxyphenyl)-7-hydroxy-4Hchromen- 4-one, sitosterol, naringenin, adenosine, plo, and beta-sitosterol as potential key compounds, and AKT1, MMP9, SRC, TNF, ESR1, NF-κB, and PPARG as potential key targets. KEGG and GO analyses revealed that the therapeutic effect of BGT on liver fibrosis may be associated with the PI3K-AKT and MAPK signaling pathways, as well as cell apoptosis, protein phosphorylation, and inflammation. Molecular docking demonstrated high-affinity binding of the identified targets to the active compounds. Additionally, molecular dynamics simulation further confirmed that the bindings of AKT1-beta-sitosterol and MMP9-quercetin exhibited good stability.</p><p><strong>Conclusions: </strong>The potential of BGT in alleviating liver fibrosis may be attributed to a combination of various active compounds, targets, and pathways. These results could support the use of BGT in treating liver fibrosis and facilitate the development of new drug candidates for this condition.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775796","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}

{"title":"Study on the Mechanism of Alpinia officinarum Hance in the Improvement of Insulin Resistance through Network Pharmacology, Molecular Docking and in vitro Experimental Verification.","authors":"Mingyan Zhou, Xiuxia Lian, Xuguang Zhang, Jian Xu, Junqing Zhang","doi":"10.2174/0115734099325919241025023026","DOIUrl":"https://doi.org/10.2174/0115734099325919241025023026","url":null,"abstract":"<p><strong>Background: </strong>Research has elucidated that the pathophysiological underpinnings of non-alcoholic fatty liver disease and type 2 diabetes mellitus are intrinsically linked to insulin resistance (IR). However, there are currently no pharmacotherapies specifically approved for combating IR. Although Alpinia officinarum Hance (A. officinarum) can ameliorate diabetes, the detailed molecular mechanism through which it influences IR has not been fully clarified.</p><p><strong>Aims: </strong>To predict the active components of A. officinarum and determine the mechanism by which A. officinarum affects IR.</p><p><strong>Methods: </strong>The active compounds and molecular mechanism underlying the improvement of IR by A. officinarum were predicted via network pharmacology and molecular docking. To further substantiate these predictions, an in vitro model of IR was induced in HepG2 cells using high glucose concentrations. Cytotoxicity and oxidative stress levels were evaluated using Cell Counting Kit-8, reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) assay kits. The putative molecular mechanisms were corroborated through Western blot and RT-PCR analyses.</p><p><strong>Results: </strong>Fourteen principal active components in A. officinarum, 133 potential anti-IR gene targets, and the top five targets with degree values were ALB, AKT1, TNF, IL6, and VEGFA. A. officinarum was posited to exert its pharmacological effects on IR through mechanisms involving lipid and atherosclerosis, the AGE-RAGE signaling pathway in diabetic complications, the PI3K-AKT signaling pathway, fluid shear stress, and atherosclerosis. Intriguingly, network pharmacology analysis highlighted (4E)-7-(4-hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3- one (A14) as the most active compound. Molecular docking studies further confirmed that A14 has a strong binding affinity for the main targets of PI3K, AKT, and Nrf2. The experiments demonstrated that A14 significantly diminished the ROS and MDA levels while augmenting the SOD activity. Moreover, A14 was found to elevate the protein expression of PI3K, AKT, Nrf2, and HO-1, and increase the mRNA levels of these targets as well as NQO1.</p><p><strong>Conclusion: </strong>A. officinarum could play a therapeutic role in IR through multiple components, targets, and pathways. The most active component of A. officinarum responsible for combating IR is A14, which has the ability to regulate oxidative stress in IR-HepG2 cells by activating the PI3K/AKT/Nrf2 pathway. These findings suggest a potential pharmacological intervention strategy for the treatment of IR.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570695","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}