Current computer-aided drug design最新文献

{"title":"A Multiscale Computational Study for the Identification of Novel Inhibitors Targeting Tau-Tubulin Kinase 1 (TTBK1) in Alzheimer's Disease.","authors":"Prashant Kurkute, Sumit Sonawane, Kumar Pratyush, Bhushan Dravyakar, Azim Ansari, Pradip Bawane, Yogeeta O Agrawal, Mahendra Khairnar, Mohd Usman Mohd Siddique","doi":"10.2174/0115734099366145250526081959","DOIUrl":"https://doi.org/10.2174/0115734099366145250526081959","url":null,"abstract":"<p><strong>Introduction: </strong>Excessive phosphorylation of tau protein by the tau-tubulin kinase 1 (TTBK1) enzyme is implicated in the pathogenesis of several neurodegenerative diseases. Based on a comprehensive literature review and availability of the co-crystal structure of TTBK1 in complex inhibitor (pdb id 4BTK), we designed a multiscale computational approach to identify novel hits from the ZINC13 chemical library.</p><p><strong>Methods: </strong>The High-Throughput Virtual Screening (HTVS) of the ZINC13 database (containing 13,195,609 molecules) was carried out against TTBK1 protein (PDB id 4BTK). Top-scoring molecules and reference molecules were further subjected to MD simulations, PCA analysis, DCCM assay, binding free energies calculations, and in-silico ADME calculations.</p><p><strong>Results: </strong>From a preliminary HTVS study, six molecules were identified based on their docking scores: ZINC37289024, ZINC89755080, ZINC20993115, ZINC72445968, ZINC28247630, and ZINC16638515, with the docking score of -10.186, -09.229, -09.045, -09.021, -08.920 and -08.821, respectively. In subsequent MD simulations studies, the protein backbone RMSD values were observed to be 1.978, 1.8178, 2.2309, 1.7933, 1.8837, 1.9461, and 1.8711 Å, respectively. Similarly, the protein backbone RMSF values were 0.9511, 1.0172, 1.2023, 1.0591, 1.0029, 1.9755, and 0.9200 Å, respectively. PCA, DCCM, and MMGBSA analysis indicated that these complexes were quite stable throughout the 100 ns MD simulations. In-silico ADME predictions of identified top six hits suggested that these top six hits possess favorable drug-like properties, supporting their potential as the lead candidates for therapeutic development.</p><p><strong>Conclusion: </strong>A multiscale molecular modelling approach was employed, and six top-scoring hits were identified as promising TTBK1 inhibitors. Analysis of the in-silico data suggested that ZINC37289024 would be the most promising clinical candidate for AD. However, further in-vitro and in-vivo experimental data would be needed for validation of these results.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546624","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":"A Comprehensive Molecular Dynamic Simulation Study of Plant Bioactive Phytoconstituents as Inhibitors for SARS-CoV-2 Main Protease and Spike (S) Glycoprotein.","authors":"Vinay Mohan Kandpal, Apoorv Tiwari, Pranabesh Mandal, Durg Vijay Singh, Gohar Taj, Sandhya Upadhyay","doi":"10.2174/0115734099285818240626110217","DOIUrl":"https://doi.org/10.2174/0115734099285818240626110217","url":null,"abstract":"<p><strong>Background: </strong>Since the commencement of the COVID-19 pandemic, researchers have been earnestly exploring the capacity of diverse bioactive compounds present in plants to impede the transmission of SARS-CoV-2. Plants have always held a special place in scientific research as invaluable bio-factories capable of producing a diverse array of chemical compounds with promising therapeutic applications. Cichorium intybus is among these plants, known for its rich reservoir of bioactive phytoconstituents with significant potential for variable health benefits.</p><p><strong>Objective: </strong>The current work aims to investigate the antiviral activity of various phytoconstituents against SARS-CoV-2 by inhibiting the main protease (Mpro) (PDB code: 6LU7) and spike (S) glycoprotein receptor binding domain (RBD) to Angiotensin-converting enzyme 2 (ACE2) (PDB code: 6M0J) of SARS-CoV-2 and Omicron main protease (PDB code: 7TOB).</p><p><strong>Methods: </strong>Auto Dock Vina was employed as the docking engine for the evaluation and determination of docking scores. To test whether a chemical satisfies the requirements for an active drug taken orally in humans, the rule of five (Ro5) was calculated. By choosing the proteinligand complex geometry having the highest affinities (highest negative Gibbs' free energy of binding/G), the docking score was calculated. The FDA-recommended antimalarial medications chloroquine and hydroxychloroquine sulfate, Remdesivir, and the antiviral medication nelfinavir were utilized as comparisons.</p><p><strong>Results: </strong>The results demonstrate that as spike glycoprotein inhibitors, crepidiaside B, 3,5-Dicaffeoylquinic acid, 4,5 -Dicaffeoylquinic acid, and crepidiside A performed better than nelfinavir, chloroquine, hydroxychloroquine sulfate, and remdesivir. The sequence of chemical reactivity of the chosen bioactive phytoconstituents, as determined by quantum chemical DFT calculations, was Crepidiside A <Crepidiaside B < 4,5-Dicaffeoylquinic acid < 3,5 -Dicaffeoylqu inic acid. The C=O portions of all isolated compounds favor an electrophilic assault, while the O-H sections are ideal for a nucleophilic attack. Additionally, Homo- Lumo values for the chosen compounds showed a noteworthy and satisfactory profile. Furthermore, the molecular dynamics simulation confirmed the stable nature of protein-ligand interaction and highlighted the amino acid residues implicated in binding.</p><p><strong>Conclusion: </strong>The current investigation discovered bioactive phytoconstituents derived from plants that have the potential to be developed as therapeutic alternatives for COVID-19.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556234","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":"Investigation of Novel Etoricoxib Analogues as Potential COX-II Inhibitors through a Bioisosteric Strategy, ADMET Evaluations, Docking Studies, and Molecular Dynamics Simulations.","authors":"Girija Prasad Swain, Sanmati Kumar Jain, Ajay Kumar Gupta, Dipti Pal, Neeraj Kumar","doi":"10.2174/0115734099379023250616054957","DOIUrl":"https://doi.org/10.2174/0115734099379023250616054957","url":null,"abstract":"<p><strong>Background: </strong>Inflammation is a natural process; however, chronic inflammation may result in numerous health issues. Etoricoxib (ETX), a selective cyclooxygenase-2 (COX-2) inhibitor, serves as an anti-inflammatory agent for various types of arthritis. However, prolonged use of ETX is associated with several adverse effects, including cardiovascular toxicity.</p><p><strong>Objective: </strong>The current research aims to design an analogue of ETX having superior pharmacokinetic properties and safer toxicological profiles employing the bioisosteric approach.</p><p><strong>Methods: </strong>The bioisosteres of various groups in ETX were produced utilizing the MolOpt online tool, resulting in the generation of novel ETX analogues. The pharmacokinetics (ADME) and toxicological profiles of the generated analogues were calculated by ADMETLab 3.0 server. The druglikeness (DL) and drugscore (DS) were calculated using OSIRIS property explorer (PEO). The molecular docking analysis of the ETX analogues against the target protein (PDB ID: 5KIR) was carried out using AutoDock Vina, and their results were visualized by Discovery Studio 2021. Molecular Dynamics (MD) simulation of the top three complexes was conducted using the Schrödinger suite. Binding free energy for the A098-5KIR, A188-5KIR, and D121- 5KIR complexes was conducted using MM-GBSA/PBSA method.</p><p><strong>Results: </strong>A total of 1200 ETX bioisosteres were produced; among them, 51 were screened on the basis of ADMET profile, DL, and DS scores and selected for the docking study. A docking study revealed that 12 analogues show good interactions and docking scores. Furthermore, the molecular dynamics simulation of ligands A098, A188, and D121 demonstrated stability throughout the 100 ns simulation period.</p><p><strong>Conclusion: </strong>The findings of the ADMET study, DL, DS, docking study, MD simulation, and binding free energy calculation indicate that the analogues A098, A188, and D121, which are bioisosteres of ETX, may serve as potential anti-inflammatory agents for inflammation-related disorders.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546625","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":"Validation of the Mechanism of Action of Jiedu Shengji Oil in the Treatment of Radiation Dermatitis based on Network Pharmacology and In Vivo Experiments.","authors":"Weishan He, Guangmei Deng, Wenya Liu, Long Kou, Fasheng Wu","doi":"10.2174/0115734099370851250512074033","DOIUrl":"https://doi.org/10.2174/0115734099370851250512074033","url":null,"abstract":"<p><strong>Background: </strong>Radiation Dermatitis (RD) is a common complication of radiation therapy, with approximately 90% of patients experiencing moderate to severe radiation dermatitis injury after radiotherapy. Jiedu Shengji oil (JDSJY) is a commonly used herbal topical preparation in our hospital, with remarkable clinical efficacy in treating radiation dermatitis. However, the mechanism of JDSJY in treating RD is unclear.</p><p><strong>Aims: </strong>The aim of the study is to explore JDSJY's mechanism of action in treating RD through methods, such as network pharmacology and in vivo experiments.</p><p><strong>Methods: </strong>The active components and disease targets of JDSJY were screened and intersected via network pharmacology for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The pharmacodynamics of JDSJY was evaluated by establishing a rat model of RD.</p><p><strong>Results: </strong>Network pharmacology showed that the pathway network of JDSJY action involved 64 targets and 6 pathways and might act by targeting key targets, such as C-reactive protein (CRP) and regulating the MAPK signalling pathway. In addition, in vivo experiments showed that JDSJY reduced skin inflammation and inhibited apoptosis, significantly ameliorated mitochondrial damage in keratinocytes, and reduced the levels of antioxidant-related indicators.</p><p><strong>Conclusion: </strong>Comprehensive network pharmacology and in vivo experiments revealed that JDSJY's therapeutic efficacy in RD is mediated by ameliorating oxidative stress and maintaining mitochondrial homeostasis in keratinocytes.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103359","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":"Screening of the Prodiginine Molecules as BH3-Mimetics against the Developed Bcl-2 Antiapoptotic Chemotherapeutic Resistance: A Molecular Docking and ADMET Study Supported by Molecular Dynamics Simulations.","authors":"Ayoub El Abbassi, Salaheddine Redouane, Zineb Azoubi, Nadia Zougagh, Assia Mouslim, Mohammed Menggad","doi":"10.2174/0115734099367809250407094437","DOIUrl":"https://doi.org/10.2174/0115734099367809250407094437","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy remains a primary treatment for stopping cancer cell growth. Unfortunately, resistance to chemotherapy is a challenge that leads to cancer relapse. Overexpression of the antiapoptotic proteins is a major cause of this resistance. BH3 mimetic compounds were developed in this work to deal with this issue by blocking the Bcl-2 antiapoptotic proteins. Currently, only a few BH3 mimetics are approved drugs, and even fewer can effectively target all antiapoptotic Bcl-2 proteins.</p><p><strong>Objective: </strong>The present study aimed to explore and screen the prodiginine family of molecules for new potential and effective BH-3 mimetics.</p><p><strong>Methods: </strong>Molecular docking and molecular dynamics (MD) simulations were used to assess the potential of 30 prodiginine analogs as BH3 mimetics, including the obatoclax molecule, a prodiginine member used in clinical trials as a BH3 mimetic.</p><p><strong>Results: </strong>Molecular docking results showed four prodiginines to have lower free binding energy values for five Bcl-2 proteins (Bcl-2, Mcl-1, Bcl-w, Bcl-xl, and Bfl1) compared to the reference drug, obatoclax. The five analogs presented safe pharmacological profiles according to Lipinski's rule of five. Furthermore, MD simulations demonstrated butylcycloheptyl prodiginine- Bcl-2 and prodigiosin-R2-Bcl-xl complexes to be more stable than the reference complexes obatoclax-Bcl-2 and obatoclax-Bcl-xl.</p><p><strong>Conclusion: </strong>Based on these results, butylcycloheptyl prodigiosin and prodigiosin-R2 could be more effective BH3 mimetics and should be further studied.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060555","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 2,4-Diaryl-6-styrylpyridine Derivatives as Orthosteric-Allosteric EGFR Inhibitors.","authors":"Harizal -, Jumina -, Harno Dwi Pranowo, Eti Nurwening Sholikhah","doi":"10.2174/0115734099370189250416024026","DOIUrl":"https://doi.org/10.2174/0115734099370189250416024026","url":null,"abstract":"<p><strong>Background: </strong>Epidermal growth factor receptor tyrosine kinase [EGFR TK] is a primary target for inhibiting cellular signal transduction in several types of cancer. Numerous EGFR TK inhibitors have been developed and approved as standard therapy for cancer management. However, the development of drug resistance and significant adverse effects have encouraged the search for alternative EGFR TK inhibitors.</p><p><strong>Objective: </strong>This study attempted to identify 2,4-diaryl-6-styrylpyridine derivatives as alternative orthosteric-allosteric EGFR TK inhibitors through molecular docking, molecular dynamic simulation, binding free energy calculation, and pharmacokinetic properties analysis.</p><p><strong>Methods: </strong>Two series of 2,4-diaryl-6-styrylpyridine derivatives were docked in orthosteric and allosteric sites of EGFR TK. Docking results were validated through molecular dynamic simulation and binding free energy calculation using YASARA Structure. Pharmacokinetic properties were analyzed using web-based free servers SwissADME and ADMETLab 3.0.</p><p><strong>Results: </strong>The molecular docking studies revealed relatively strong affinity, with binding energy ranging from -10.3 to -12.2 kcal/mol in the orthosteric site and from -8.3 to -10.9 kcal/mol in the allosteric site of EGFR TK. The proposed ligand complexes with the highest binding energy and proper hydrogen bonds showed comparable stability and binding free energy than native ligand complexes. The pharmacokinetic properties of the proposed ligands indicated relatively poor characteristics due to relatively high lipophilicity and certain toxicophores.</p><p><strong>Conclusion: </strong>This study identified NASP06 and NASP01 as the most stable orthosteric and allosteric inhibitors of EGFR TK, respectively. These findings revealed a novel class of EGFR TK inhibitors capable of interacting with both orthosteric and allosteric sites.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011946","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":"The Active Ingredients and Mechanisms of Xuefuzhuyu Pills in Treating Hyperprolactinemia Caused by Antipsychotics based on UHPLCQ-TOF-MS/MS, Network Pharmacology, and Molecular Docking Validation.","authors":"Linliu Du, Zihuan Zhang, Mingyue Liu, Xiufang Zhu, Guanli Su, Shanshan Chen, Chaoyi Li, Jianxin Wang","doi":"10.2174/0115734099366667250410061157","DOIUrl":"https://doi.org/10.2174/0115734099366667250410061157","url":null,"abstract":"<p><strong>Background: </strong>XueFuZhuYu pills (XFZY), a traditional Chinese herbal formula originated from the xuefuzhuyu decoction in Correction on Errors in Medical Classics, has a certain clinical effect on the treatment of hyperprolactinemia (HPRL) caused by antipsychotics. However, the active ingredients and mechanism by which XFZY contributes to the hyperprolactinemia caused by antipsychotics remain unclear.</p><p><strong>Objectives: </strong>The aim of the study was to investigate the molecular basis of XFZY in the therapy of antipsychotic-induced HPRL and to establish a scientific foundation for its application.</p><p><strong>Methods: </strong>First, the UHPLC-Q-TOF-MS/MS methodology was employed to perform chromatographic separation and gather mass spectrometry data. Subsequently, the preprocessed mass spectrometry data were uploaded to the Global Natural Products Social Molecular Networking (GNPS) platform for spectral library interrogation and molecular network analysis. Next, based on the detected chemical constituents and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the effective chemical components within XFZY were chosen. Swiss Target Prediction was employed to determine probable targets of components, and we used Cytoscape to create a network of components and their associated targets. After that, HPRL-related targets were found and filtered using four disease databases, and then a proteinprotein interaction (PPI) network was built using the STRING database. Cytoscape was utilized to conduct visualization and cluster analysis. Meanwhile, the Metascape database was adopted for the enrichment analysis of GO and KEGG. At last, Autodock Vina was applied to perform molecular docking between the principal components and target proteins.</p><p><strong>Results: </strong>In total, 213 compounds were discovered in XFZY. Two hundred eight active chemical components, 622 probable targets, and 242 HPRL-related target genes were identified. There were 76 common targets between the XFZY and HPRL. Following analysis, 1371 GO biological process items and 162 KEGG signal pathways were identified. The primary chemicals and target proteins exhibited great affinity in molecular docking.</p><p><strong>Conclusion: </strong>This research manifests that XFZY, as a traditional Chinese medicine formula, proffers a novel pathway for the treatment of antipsychotic-induced HPRL. We elucidated the specific molecular mechanisms underlying the anti-HPRL effects of XFZY and its active ingredients, laying a foundation for the subsequent clinical applications of this formula.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055951","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 the Ubiquitin-conjugating Enzyme for Oral Squamous Cell Carcinoma Therapy: Discovering Natural Inhibitors.","authors":"Unnati Soni, Pritish Kumar Varadwaj, Krishna Misra","doi":"10.2174/0115734099369552250401205516","DOIUrl":"https://doi.org/10.2174/0115734099369552250401205516","url":null,"abstract":"<p><strong>Background: </strong>Oral Squamous Cell Carcinoma (OSCC) is a multiple-phase carcinogenic disease that concurrently involves malignant lesions, invasion, and metastasis. It has been reported that Ubiquitin-conjugating enzymes play a significant role in the progression of OSCC and other fatal cancers through the process of ubiquitination. Among them, UBE2D1 represents a promising target for therapeutic intervention. Strategies aimed at inhibiting UBE2D1 could restore the function of tumor suppressors, such as p53, and potentially enhance the effectiveness of existing cancer therapies.</p><p><strong>Objective: </strong>This study aims to discover the potential natural inhibitors of UBE2D1 from an extensive chemical library through computational techniques.</p><p><strong>Methods: </strong>This study utilized in silico methods, such as virtual screening, molecular docking, analysis of pharmacokinetic parameters, and molecular dynamics simulation, to discover the most effective inhibitors for the ubiquitin-conjugating enzyme.</p><p><strong>Results: </strong>Based on binding affinity, the top six compounds, ZINC15113777, ZINC225461658, ZINC107430641, ZINC259440, ZINC4025306, and ZINC107283931, were found to be the best for the selected target. Also, molecular dynamic simulation results showed that all these compounds form stable complexes with UBE2D1.</p><p><strong>Conclusion: </strong>Based on our analysis of the results, we have determined that natural products, specifically ZINC15113777, ZINC4025306, and ZINC107283931, have the ability to inhibit UBE2D1 efficiently and could be utilized as potential drugs for the treatment of OSCC and other cancers. Such approaches may help to reinstate normal apoptotic pathways and improve overall treatment outcomes in patients with cancers characterized by UBE2D1 dysregulation. Additionally, conducting in-vitro/vivo studies on these molecules could be a prospective avenue in the realm of pharmaceutical research.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032096","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":"Cholinesterase Inhibition and Anticancer Properties of [4-(Benzyloxy) phenyl]{Methylidene}hydrazinylidene]-1,3-dihydro-2H-Indol-2-ones Using Swiss Target-guided Prediction.","authors":"Naseer Maliyakkal, Parham Taslimi, Burak Tuzun, Soumaya Menadi, Ercan Cacan, Asmy Appadath Beeran, Sandeep Bindra, Naresh Payyaula, Sunil Kumar, Bijo Mathew","doi":"10.2174/0115734099359621250320073543","DOIUrl":"https://doi.org/10.2174/0115734099359621250320073543","url":null,"abstract":"<p><strong>Introduction: </strong>Our group previously reported isatin-based hydrazones (ISB1-ISB6) were further evaluated for their in vitro acetylcholine esterase, butylcholinestrase and cytotoxic effects on cancer cell lines. The compounds successfully suppressed AChE and BChE, with Ki values ranging from 1.06±0.07 to 23.57±1.64 nM for AChE and 15.31±1.28 to 84.41±8.04 nM for BChE. However, the IC50 values of these compounds for AChE and BChE were found to be in the ranges of 1.45-25.51 nM and 16.38-92.90 nM, respectively.</p><p><strong>Method: </strong>Furthermore, to explore the anti-tumor potential of our newly synthesized compounds, we conducted a cytotoxic MTT assay to assess their impact on two different cancer cell lines: MCF7 and A2780.</p><p><strong>Results: </strong>Our findings highlight diverse cytotoxic profiles among the compounds. Specifically, ISB2, ISB3, and ISB4 demonstrated potential cytotoxicity in the A2780 cell line, while ISB6 exhibited significant cytotoxicity in the MCF7 cell line. This suggests that these compounds have different effects on cancer cell types, indicating the need for further investigation into their potential applications in cancer therapy.</p><p><strong>Conclusion: </strong>Finally, molecular docking and dynamic study revealed that lead molecule ISB3 provides stability in the AChE and BChE protein-ligand complex.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805162","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":"Discovery of Polyphenolic Compounds from Mangifera indica as Potent Therapeutics for Strongyloides stercoralis Infection via Computer-aided Drug Design.","authors":"Samson Olusegun Afolabi, Abel Kolawole Oyebamiji, Omowumi Temitayo Akinola, David O Adekunle, Ehimen Anastasia Erazua, Ayodeji Arnold Olaseinde, Adesoji Alani Olanrewaju, Oluwakemi Ebenezer, Viacheslav Kravtsov, Ekaterina Skorb, Sergey Shityakov","doi":"10.2174/0115734099353596250313020805","DOIUrl":"https://doi.org/10.2174/0115734099353596250313020805","url":null,"abstract":"<p><strong>Background: </strong>The global spread of Strongyloides stercoralis has escalated public health concerns, affecting over 600 million people worldwide. The rise in global migration has heightened the risk of transmission, underscoring the urgent need for effective treatment options.</p><p><strong>Objective: </strong>This study aimed to investigate ten polyphenolic phytochemicals derived from Mangifera indica as potential alternatives to combat S. stercoralis.</p><p><strong>Methods: </strong>The efficacy of these compounds was evaluated using computational techniques, including density functional theory (DFT) analysis, molecular docking, adsorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment, and molecular dynamics (MD) simulations.</p><p><strong>Results: </strong>DFT calculations revealed significant chemical reactivity in compounds such as kaempferol, ellagic acid, quercetin, norathyriol, mangiferin, and ferulic acid. Molecular docking identified mangiferin, quercetin, kaempferol, and norathyriol as top candidates for targeting S. stercoralis. A 200-ns MD simulation of the protein-ligand complex demonstrated the stability and binding behavior of these compounds compared to the reference drug, thiabendazole. ADMET screening confirmed their drug-likeness. Notably, quercetin and mangiferin exhibited strong binding affinities (ΔGbind = -42.35 and -54.57 kcal/mol, respectively), outperforming thiabendazole (ΔGbind = -28.94 kcal/mol).</p><p><strong>Conclusion: </strong>Quercetin and mangiferin emerge as promising alternatives to thiabendazole, offering favorable chemical reactivity, potent inhibition constants, and strong biological activity for the treatment of S. stercoralis.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702542","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}