Current computer-aided drug design最新文献

{"title":"Designing and Evaluation of a Novel IL-1RA Fusion Cytokine to Enhance the Pharmacokinetics and Receptor Affinity for Better Therapeutic Intervention in Inflammatory Disorders.","authors":"Anith Kumar Rajendran, Kalimuthu Karuppanan, Senthilkumar Palanisamy","doi":"10.2174/0115734099352664250225041948","DOIUrl":"https://doi.org/10.2174/0115734099352664250225041948","url":null,"abstract":"<p><strong>Introduction: </strong>The extended IL-1 activity is implicated in autoimmune disorders, such as rheumatoid arthritis, diabetes mellitus, and Parkinson's disease, as well as delayed wound healing. Additionally, it can result in cytokine storms during pathogenic infections.</p><p><strong>Methods: </strong>The regulation was carried out by Interleukin-1 receptor antagonist (IL-1RA), a key anti-inflammatory molecule. IL-1RA serves as a decoy protein that competes with Interleukin-1 receptors (IL-1RI and IL-1RII) for binding, effectively counteracting the activity of Interleukin- 1 (IL-1). The deficiency was substantiated by commercially available recombinant IL-1RA called Anakinra. The main problem with the existing drug is that it has less pharmacokinetics and reduced binding affinity to its receptor, which requires frequent administration of the drug. To overcome these drawbacks, we have designed a new fusion protein by adding an Fc fragment of Human IgGI fused with IL-1RA using a linker in between, and the design aimed to transport the protein into the N-glycosylation pathway. These characteristic features increase the pharmacokinetics, solubility, and binding efficiency of the protein. As the protein was designed to be expressed in a eukaryotic system, to understand the possibility of the proposed hypothesis, we used machine learning-based AlphaFold2 to model the protein structure and molecular simulation studies to understand the functional integrity of the designed protein.</p><p><strong>Results: </strong>The in silico results showed that the modeled fusion protein structure has very good binding to its receptor with the support of 21 H bonds and 7 salt bridges and maintained the binding stability over the MD simulations.</p><p><strong>Conclusion: </strong>These findings support fusion protein's potential as a promising and stable therapeutic candidate.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569065","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":"In Silico Identification of Emblica officinalis Compounds Inhibiting Thermolabile Hemolysin from Vibrio alginolyticus in Shrimp.","authors":"Sayed Mashequl Bari, Meamaching Marma, Nafees Bin Reza, Sk Faisal Ahmed, Shoriful Islam, Nafis Rayhan, Md Alomgir Hossian, Md Matiur Rahman, Md Saiful Alam","doi":"10.2174/0115734099342492250120114644","DOIUrl":"10.2174/0115734099342492250120114644","url":null,"abstract":"<p><strong>Background: </strong>Thermolabile hemolysin (TLH) is a key virulent protein of Vibrio alginolyticus, known for its hemolytic and phospholipase activities, leading to shrimp vibriosis disease. It has been suggested as a potential therapeutic candidate for vibriosis therapy.</p><p><strong>Methods: </strong>Computational studies, including molecular docking, toxicity analysis, and molecular dynamics (MD) simulations, were conducted to investigate the inhibition of the phospholipase activity of TLH by phytochemicals from Emblica officinalis.</p><p><strong>Results: </strong>Out of the twenty-nine compounds, the top three, including Ellagic acid (CID 5281855), Quercetin (CID 5280343), and Kaempferol (CID 5280863), were sorted based on their highest molecular docking scores of -9.2, -8.9, and -8.8, respectively. Subsequently, molecular dynamics (MD) simulations of these selected leads were performed to observe the structural stability of these compounds in the binding sites of TLH protein. The MD simulation outcomes indicated that all three compounds demonstrated superior stability throughout 100 nanoseconds compared to the control compound Resveratrol. The molecular simulation results suggest stable interactions, with average root-mean-square deviation (RMSD) and root-meansquare fluctuation (RMSF) values of 1-2 Å and 0-3 Å. Pharmacokinetic and toxicity analyses were conducted to evaluate the suitability and toxicity of these selected compounds. All top three compounds passed the Lipinski rule, and toxicity criteria.</p><p><strong>Conclusion: </strong>Therefore, these compounds have the potential to serve as effective therapeutics for controlling Vibrio alginolyticus infection in shrimp.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461255","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":"Network Pharmacology and Experimental Validation to Reveal the Pharmacological Mechanisms of Gynostemma pentaphylla against Acute Pharyngitis.","authors":"Juan Zhong, Xiaozhong Wu, Chunxi Huang, Yongqiang Li, Min Huang, Liuyan Xu, Jianfeng Lu, Lili Pang, Qiuju Huang, Jing Chen","doi":"10.2174/0115734099324793250116133159","DOIUrl":"https://doi.org/10.2174/0115734099324793250116133159","url":null,"abstract":"<p><strong>Background: </strong>Acute pharyngitis (AP) is a prevalent ailment. Gynostemma pentaphylla (GP), a traditional Chinese medicine (TCM), may treat AP due to its anti-tumor and anti-inflammatory properties, but this remains unexplored.</p><p><strong>Methods: </strong>This study utilized the TCMSP and Swiss Target Prediction databases to analyze GP's chemical composition and target proteins. The Genecards database was used to identify targets relevant to AP. A PPI network diagram of drug-disease intersection targets was created using the STRING database, and Cytoscape was utilized to create a network visualization diagram of \"GP active components-targets-AP\" in order to determine key active components of GP in treating AP. Gene ontology (GO) and biological pathway (KEGG) enrichment analyses were conducted on targets in the David database. Molecular docking verification of key targets and components was performed using AutoDock Vina software. In animal experiments, a rat model of AP was induced by a 15% concentrated ammonia solution, and HE staining was conducted to observe histopathological changes in the rat pharynx after intragastric administration of Houyanqing. ELISA was used to detect expression levels of serum interleukin-1-beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α).</p><p><strong>Results: </strong>A total of 18 active ingredients were screened from GP, among which Ruvoside _ qt, Rhamnazin, 3 ' -methyleriodictyol, and sitosterol were five key active ingredients. The key targets involved EGFR, STAT3, MAPK3, SRC, AKT1, etc. KEGG enrichment analysis showed that GP mainly acted on Pathways in cancer, P13K-AKT signaling Pathways, JAK-STAT signaling pathways, and other signaling pathways. Molecular docking results showed that four core compounds and five key targets met the energy matching. Animal experiments showed that compared with the normal group, the expression levels of IL-1β, IL-6, and TNF-α in the AP model group were significantly up-regulated (P < 0.05). In addition, compared with the model group, intragastric administration of the dexamethasone group and gypenosides group could alleviate the up-regulation of inflammatory factors in model rats, and the levels of IL-1β, IL-6, and TNF-α were decreased (P < 0.05).</p><p><strong>Conclusion: </strong>This study predicted the possible targets of GP in the treatment of AP through network pharmacology. The results suggest that gypenosides may inhibit the expression of inflammatory factors by regulating Pathways in cancer, P13K-AKT, and JAK-STAT signaling pathways to treat AP.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367050","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":"Qi-Gui-Jian-Gu Decoction Accelerates Osteogenesis and Fracture Healing by Activating the Wnt/β-Catenin Signaling Pathway.","authors":"Siluo Wu, Jiayang Wang, Ziheng Luo, Bifeng Li, Liangliang Xu, Liuchao Hu, Rihe Hu","doi":"10.2174/0115734099345441250121101413","DOIUrl":"https://doi.org/10.2174/0115734099345441250121101413","url":null,"abstract":"<p><strong>Background: </strong>Qi-Gui-Jian-Gu decoction (QGJG), as a clinical empirical formula, has clinical benefits in promoting bone formation, but the underlying mechanism for its application in treating fractures has not been investigated.</p><p><strong>Methods: </strong>The potential therapeutic target and signaling pathway of QGJG for treating fractures were analyzed by network pharmacology. In vitro, we used bone marrow mesenchymal stem cells (MSCs) to evaluate osteogenic differentiation and mineralization by alizarin red staining, quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunofluorescence staining. In vivo, the 8w male SPF C57BL/6J mouse femoral fracture model was constructed, and the therapeutic effects of QGJG were evaluated.</p><p><strong>Results: </strong>By network pharmacology analysis, we found that glycogen synthase kinase 3 beta (GSK3β) was a potential therapeutic target of QGJG for treating fractures. The canonical Wnt signaling pathway was selected as the potential molecular mechanism. QGJG was confirmed to upregulate the mRNA levels of alkaline phosphatase (ALP) and bone morphogenetic protein 2 (BMP2), thereby promoting osteogenic differentiation and mineralization. Mechanistically, QGJG inhibited GSK3β while increasing p-Ser9-GSK3β to increase β-catenin protein expression and its nuclear translocation, implying the activation of the canonical Wnt signaling pathway. In vivo, QGJG administration promoted fracture healing, as demonstrated by the up-regulation of OPN and Osx, and accelerated the progression of ossification at 2 and 3 weeks after surgery.</p><p><strong>Conclusion: </strong>QGJG promotes osteogenic differentiation and fracture healing by activating the canonical Wnt pathway.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367062","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":"Comparative Study on Sedative and Hypnotic Effects of Crude and Parched Semen Ziziphi Spinosae: Integration of Network Pharmacology and In Vivo Pharmacological Evaluation.","authors":"Jing Xia, Ming Cai, Bo Xu, Guang-Jing Xie, Ping Wang","doi":"10.2174/0115734099281920240730051328","DOIUrl":"https://doi.org/10.2174/0115734099281920240730051328","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the medicinal properties of SZS before and after processing and provide novel insights into its potential for treating insomnia.</p><p><strong>Methods: </strong>This study employed the network pharmacology platform to gather information on the chemical composition of SZS, human targets, genes, molecular networks, and pathways associated with insomnia treatment using SZS. Liquid chromatography-tandem mass spectrometry (LC-MS/ MS) was utilized to analyze the chemical profiles of crude SZS, parched SZS, and their combined decoction. The effects of different SZS products on p-chlorophenylalanine-induced insomnia mice were evaluated through pentobarbital-induced sleep tests, behavioral analyses, examination of brain tissue-related mRNA levels, and measurement of plasma neurotransmitters, aiming to explore the sedative and hypnotic effects of various SZS products.</p><p><strong>Results: </strong>SZS was found to contain a total of 47 genes, including 22 target genes associated with insomnia. These genes may contribute to the sedative and hypnotic effects through 9 related pathways and 69 biological processes. The active components of SZS remained consistent before and after processing. Jujuboside B was found in higher concentrations in crude SZS, while jujuboside A was more abundant in parched SZS. Additionally, SZS exhibited reduced locomotor activity in mice, enhanced the hypnotic effect of pentobarbital sodium, and decreased the levels of acetylcholinesterase, α-1B adrenergic receptor, and solute carrier family 6 member 4 mRNA in the cortex and hippocampus of mice. The levels of acetylcholine, choline acetyltransferase, 5-hydroxyindoleacetic acid, and glutamate in plasma increased, with the hypnotic effect being proportional to the dosage of the drug.</p><p><strong>Conclusion: </strong>SZS demonstrates sedative and hypnotic effects, potentially mediated by its influence on neurotransmitter levels and related receptors within the central nervous system. There was a slight variation in regulatory capabilities before and after SZS processing, with the combined decoction of crude and parched SZS exhibiting a more pronounced effect, particularly at higher dosages.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026104","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 Evaluation of Punica granatum Leaf Phytochemicals against Multi-drug Resistant E. coli: Molecular Docking, ADMET, MD Simulation, and DFT Studies.","authors":"Shivam Mishra, Shristi Modanwal, Prabhat Kumar, Ashutosh Mishra, Nidhi Mishra","doi":"10.2174/0115734099343126241105102839","DOIUrl":"https://doi.org/10.2174/0115734099343126241105102839","url":null,"abstract":"<p><strong>Introduction: </strong>Multidrug-resistant (MDR) E. coli presents a significant challenge in clinical settings, necessitating the exploration of novel therapeutic agents. Phytochemicals from Punica granatum (pomegranate) leaves have shown potential antibacterial properties. This study aims to identify and evaluate the efficacy of these phytochemicals against MDR E. coli.</p><p><strong>Objectives: </strong>This study aims to identify and evaluate the efficacy of most potential phytochemical of Punica granatum leaf against MDR E. coli. through molecular docking, adme, toxicity, molecular dynamic simulation, MMPBSA and DFT approaches.</p><p><strong>Methods: </strong>We performed molecular docking of 11 phytochemicals from the IMPPAT database with four MDR E. coli targets: 1AJ6, 1FJ8, 4BJP, and 6BU3. Granatin B demonstrated the best binding affinity and was further analyzed. ADME (Absorption, Distribution, Metabolism, and Excretion) and toxicity analyses were conducted to assess its pharmacokinetic properties and safety profile. Molecular Dynamics (MD) simulations were performed to evaluate the stability of Granatin B with the targets. Finally, density functional theory (DFT) analysis was carried out to understand the electronic properties and reactivity of Granatin B.</p><p><strong>Results: </strong>Granatin B exhibited the highest binding affinity among the 11 phytochemicals, indicating strong potential as an inhibitor of MDR E. coli. ADME analysis revealed favorable pharmacokinetic properties and toxicity analysis confirmed that Granatin B is non-toxic. MD simulations showed stable interactions between Granatin B and all four targets. DFT analysis provided insights into the electronic properties and reactive sites of Granatin B, supporting its potential mechanism of action.</p><p><strong>Conclusion: </strong>Granatin B from Punica granatum leaves is a promising candidate for treating MDR E. coli infections. The integration of molecular docking, ADME, toxicity, MD simulations, and DFT analysis underscores its therapeutic potential and paves the way for further experimental validation and development as a novel antibacterial agent.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980945","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":"Identification of a ceRNA Network Regulating Malignant Transformation of Isocitrate Dehydrogenase Mutant Astrocytoma: An Integrated Bioinformatics Study.","authors":"Yaqian Cui, Hongquan Zheng, Zhengwei Zhou, Suo Liu, Mingxue Shen, Runze Qiu, Xiong Zhang, Yingbin Li, Hongwei Fan","doi":"10.2174/0115734099293010240810181446","DOIUrl":"https://doi.org/10.2174/0115734099293010240810181446","url":null,"abstract":"<p><strong>Introduction: </strong>Astrocytoma is the most common glioma, accounting for about 65% of glioblastoma. Its malignant transformation is also one of the important causes of patient mortality, making it the most prevalent and difficult to treat in primary brain tumours. However, little is known about the underlying mechanisms of this transformation.</p><p><strong>Methods: </strong>In this study, we established a ceRNA network to screen out the potential regulatory pathways involved in the malignant transformation of IDH-mutant astrocytomas. Firstly, the Chinese Glioma Genome Atlas (CGGA) was employed to compare the expression levels of the differential expressed genes (DEGs) in astrocytomas. Then, the ceRNA-regulated network was constructed based on the interaction of lncRNA-miRNA-mRNA. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore the main functions of the differentially expressed genes. COX regression analysis and log-rank test were combined to screen the ceRNA network further. In addition, quantitative real-time PCR (qRT-PCR) was conducted to identify the potential regulatory mechanisms of malignant transformation in IDH-mutant astrocytoma. We constructed a ceRNA network with 34 lncRNAs, 29 miRNAs, and 71 mRNAs.</p><p><strong>Results: </strong>GO and KEGG analyses results suggested that DEGs were associated with tumor-associated molecular functions and pathways. In addition, we screened two ceRNA regulatory networks using Cox regression analysis and log-rank test. QRT-PCR assay identified the NAA11/hsa- miR-142-3p/GS1-39E22.2 regulatory axis of the ceRNA network to be associated with the malignant transformation of IDH-mutant astrocytoma.</p><p><strong>Conclusion: </strong>The discovery of this mechanism deepens our understanding of the molecular mechanisms of malignant transformation in astrocytomas and provides new perspectives for exploring glioma progression and targeted therapies.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960685","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":"Targeting PD-1 in Squamous Cell Carcinoma: Flavonoid-based Therapeutics Unveiled through in silico and in vitro Approaches.","authors":"Neha Sharma, Rupa Mazumder, Pallavi Rai, Abhijit Debnath","doi":"10.2174/0115734099312638240830060525","DOIUrl":"https://doi.org/10.2174/0115734099312638240830060525","url":null,"abstract":"<p><strong>Introduction: </strong>Squamous cell carcinoma is a major public health concern, with traditional treatments such as surgery, chemotherapy, and radiation therapy frequently resulting in significant side effects. Immunotherapy targeting checkpoints such as PD-1, CTLA-4, and B7- H3 provides a more specific approach but incurs high costs due to monoclonal antibodies.</p><p><strong>Aim and objective: </strong>This study aims to investigate the potential of natural flavonoids as lowtoxicity, small molecule-based alternatives targeting the PD-1 immunological checkpoint for SCC treatment. It aims to identify and evaluate flavonoid compounds from the NPACT database for their efficacy through in silico and in vitro screenings.</p><p><strong>Method: </strong>Employing a comprehensive in silico approach, including SBVS, Drug Likeness, Toxicity Prediction, Consensus Molecular Docking, DFT, and 300 ns MD simulations, this study screened for flavonoids with high affinity to PD-1. Identified lead molecules were further validated through in-vitro assays, such as NRU, to assess their anticancer activities.</p><p><strong>Result: </strong>The flavonoid NPACT01407 showed high affinity for PD-1, favorable drug-like properties, low toxicity, and effective stability at the active site, along with an optimal IC50 value, highlighting its potential as an effective immunotherapeutic agent for SCC.</p><p><strong>Conclusion: </strong>The study highlights the potential of the flavonoid molecule NPACT01407 as a promising candidate for the immunotherapeutic treatment of Squamous cell carcinoma. These findings provide a solid basis for further experimental validation and drug development efforts, suggesting a novel, less toxic, and cost-effective approach to cancer treatment.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960686","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":"Identification of Potential Inhibitors of Three NDM Variants of <i>Klebsiella</i> Species from Natural Compounds: A Molecular Docking, Molecular Dynamics Simulation and MM-PBSA Study.","authors":"Nakul Neog, Minakshi Puzari, Pankaj Chetia","doi":"10.2174/0115734099294294240311061115","DOIUrl":"10.2174/0115734099294294240311061115","url":null,"abstract":"<p><strong>Background: </strong><i>Klebsiella</i> species have emerged as well-known opportunistic pathogens causing nosocomial infections with β-lactamase-mediated resistance as a prevalent antibiotic resistance mechanism. The discovery and emergence of metallo-β-lactamases, mainly new- Delhi metallo-β-lactamases (NDMs), have increased the threat and challenges in healthcare facilities.</p><p><strong>Objectives: </strong>A computational screening was conducted using 570 natural compounds from Dr. Duke's Phytochemical and Ethnobotanical data to discover promising inhibitors for NDM-6, NDM-9, and NDM-23 of the <i>Klebsiella</i> species.</p><p><strong>Methods: </strong>Using homology modeling on the Raptor-X web server, the structures of the three NDM variants were predicted. The structures were validated using various computational tools and MD simulation for 50 ns. Lipinski - Vebers' Filter and ADMET Screening were used to screen 570 compounds, followed by docking in Biovia Discovery Studio 2019 using the CDOCKER module. GROMACS was used to simulate the compounds with the highest scores with the proteins for 50 ns. Using the MM-PBSA method and g_<i>mmpbsa</i> tool, binding free energies were estimated and per-residue decomposition analysis was conducted.</p><p><strong>Results: </strong>The three structures predicted were found stable after the 50 ns MD Simulation run. The compounds Budmunchiamine-A and Rhamnocitrin were found to have the best binding energy towards NDM-6, NDM-9, and NDM-23, respectively. From the results of MD Simulation, MM-PBSA binding free energy calculations, and per-residue decomposition analysis, the Protein-ligand complex of NDM-6 with Budmunchiamine A and NDM-9 with Rhamnocitrin was relatively more stable than the complex of NDM-23 and Rhamnocitrin.</p><p><strong>Conclusion: </strong>The study suggests that Budmunchiamine-A and Rhamnocitrin are potential inhibitors of NDM-6 and NDM-9, respectively, and may pave a path for <i>in-vivo</i> and <i>in-vitro</i> studies in the future.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"142-165"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140178332","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":"Identification of Novel Marine Bioactive Compound as Potential Multiple Inhibitors in Triple-negative Breast Cancer - An <i>in silico</i> Approach.","authors":"Hema Priya Manivannan, Vishnu Priya Veeraraghavan, Arul Prakash Francis","doi":"10.2174/0115734099287118240102112337","DOIUrl":"10.2174/0115734099287118240102112337","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer lacking specific receptors, with dysregulated and overactivated Hedgehog (Hh) and mTOR/PI3K/AKT signaling pathways as potential therapeutic targets.</p><p><strong>Objective: </strong>This study aimed to identify potential inhibitors among 53 alkaloids derived from 9 marine bryozoans using in silico approaches. It sought to analyze their impact on key signaling targets and their potential for future experimental validation.</p><p><strong>Methods: </strong>In this research, selected targets were evaluated for protein-protein interactions, coexpression survival, and expression profiles. The protein expression was validated through the Human Protein Atlas (HPA) database and druggability through DGIdb. Online web servers were employed to assess drug-likeness, physiochemical properties, pharmacokinetics, and toxicological characteristics of the compounds. Molecular docking and dynamic simulations were carried out for ligand-protein interactions. Common Pharmacophore features, bioavailability, bioactivity, and biological activity spectrum (BAS) were also analyzed.</p><p><strong>Results: </strong>Out of the 13 compounds studied, 10 displayed strong binding affinity with binding energies ranging from >-6.5 to <-8 Kcal/mol across all targets. Molecular dynamics simulations provided insights into Amathamide E's stability and conformational changes. Pharmacophore modeling revealed common features in 14 compounds potentially responsible for their biological activity.</p><p><strong>Conclusion: </strong>Our findings indicate the potential of marine-derived compounds as TNBC inhibitors. Further <i>in vitro</i> and <i>in vivo</i> validation is necessary to establish their effectiveness and explore their role as novel anti-TNBC agents.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":"375-402"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139479686","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}