Current computer-aided drug design最新文献

{"title":"Synthesis, and <i>In-silico</i> Studies of Indole-chalcone Derivatives Targeting Estrogen Receptor Alpha (ER-α) for Breast Cancer.","authors":"Rahul Charudatta Choudhari, Kamalpreet Kaur, Agnidipta Das, Vikas Jaitak","doi":"10.2174/0115734099263650230926053750","DOIUrl":"10.2174/0115734099263650230926053750","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is the prominent reason of death in women worldwide, and the cases are increasing day by day. There are many FDA-approved drugs for treating breast cancer. Due to drug resistance, and problems in selectivity, there is a need to develop more effective agents with few side effects. Indole derivatives have demonstrated significant pharmacological potential as anti-breast cancer agents. Further, chalcone derivatives incorporating heterocyclic scaffolds play a significant role in medicine. Indole-chalcone-based compounds offer the potential for improved biological activity and enhanced drug-like properties. It prompted us to explore the synthesis of Indole-Chalcone derivatives targeting estrogen receptor alpha (ER-α) to discover potent anti-breast cancer agents.</p><p><strong>Objectives: </strong>To synthesize indole-chalcone derivatives and study their binding interactions for ER-α protein by molecular docking for breast cancer treatment.</p><p><strong>Methods: </strong>In this study, indole-chalcone derivatives have been synthesized using conventional heating. With the help of Schrodinger software, molecular interaction as well as ADME (Adsorption, Distribution, Metabolism, and Excretion) studies of the compounds were conducted.</p><p><strong>Results: </strong>Among all the synthesized compounds, four compounds (1, 2, 3, and 4) showed better docking scores (-10.24 kcal/mol, -10.15 kcal/mol, -9.40 kcal/mol, -9.29 kcal/mol, respectively) than the standard tamoxifen (-8.43 kcal/mol).</p><p><strong>Conclusion: </strong>From <i>In-silico</i> studies, we can conclude that four compounds from the synthesized series fit into the active site of ER-α. ADME properties of synthesized derivatives were found in the acceptable range. In the future, these compounds can be further explored for biological activity.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54232864","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":"Molecular Modelling of Resveratrol Derivatives with SIRT1 for the Stimulation of Deacetylase Activity.","authors":"Mozhdeh Zamani, Pooneh Mokarram, Mehdi Jamshidi, Morvarid Siri, Hadi Ghasemi","doi":"10.2174/0115734099258321231003161602","DOIUrl":"10.2174/0115734099258321231003161602","url":null,"abstract":"<p><strong>Background: </strong>Resveratrol is a polyphenol that is found in plants and has been proposed to have a potential therapeutic effect through the activation of SIRT1, which is a crucial member of the mammalian NAD+ -dependent deacetylases. However, how its activity is enhanced toward specific substrates by resveratrol derivatives has not been studied. This study aimed to evaluate the types of interaction of resveratrol and its derivatives with SIRT1 as the target protein, as well as to find out the best ligand with the strangest interaction with SIRT1.</p><p><strong>Materials and methods: </strong>In this study, we employed the extensive molecular docking analysis using AutoDock Vina to comparatively evaluate the interactions of resveratrol derivatives (22 molecules from the ZINC database) as ligands with SIRT1 (PDB ID: 5BTR) as a receptor. The ChemDraw and Chem3D tools were used to prepare 3D structures of all ligands and energetically minimize them by the MM2 force field.</p><p><strong>Results: </strong>The molecular docking and visualizations showed that conformational change in resveratrol derivatives significantly influenced the parameter for docking results. Several types of interactions, including conventional hydrogen bonds, carbon-hydrogen bonds, Pi-donor hydrogen bonds, and Pi-Alkyl, were found via docking analysis of resveratrol derivatives and SIRT1 receptors. The possible activation effect of resveratrol 4'-(6-galloylglucoside) with ZINC ID: ZINC230079516 with higher binding energy score (-46.8608 kJ/mol) to the catalytic domain (CD) of SIRT1 was achieved at the maximum value for SIRT1, as compared to resveratrol and its other derivatives.</p><p><strong>Conclusion: </strong>Finally, resveratrol 4'-(6-galloylglucoside), as a derivative for resveratrol, has stably interacted with the CD of SIRT1 and might be a potential effective activator for SIRT1.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41242536","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":"Automation of Drug Discovery through Cutting-edge <i>In-silico</i> Research in Pharmaceuticals: Challenges and Future Scope.","authors":"Smita Singh, Pranjal Kumar Singh, Kapil Sachan, Mukesh Kumar, Poonam Bhardwaj","doi":"10.2174/0115734099260187230921073932","DOIUrl":"10.2174/0115734099260187230921073932","url":null,"abstract":"<p><p>The rapidity and high-throughput nature of <i>in silico</i> technologies make them advantageous for predicting the properties of a large array of substances. <i>In silico</i> approaches can be used for compounds intended for synthesis at the beginning of drug development when there is either no or very little compound available. <i>In silico</i> approaches can be used for impurities or degradation products. Quantifying drugs and related substances (RS) with pharmaceutical drug analysis (PDA) can also improve drug discovery (DD) by providing additional avenues to pursue. Potential future applications of PDA include combining it with other methods to make insilico predictions about drugs and RS. One possible outcome of this is a determination of the drug potential of nontoxic RS. ADME estimation, QSAR research, molecular docking, bioactivity prediction, and toxicity testing all involve impurity profiling. Before committing to DD, RS with minimal toxicity can be utilised in silico. The efficacy of molecular docking in getting a medication to market is still debated despite its refinement and improvement. Biomedical labs and pharmaceutical companies were hesitant to adopt molecular docking algorithms for drug screening despite their decades of development and improvement. Despite the widespread use of \"force fields\" to represent the energy exerted within and between molecules, it has been impossible to reliably predict or compute the binding affinities between proteins and potential binding medications.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41166183","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":"Identify Diabetes-related Targets based on ForgeNet_GPC.","authors":"Bin Yang, Linlin Wang, Wenzheng Bao","doi":"10.2174/0115734099258183230929173855","DOIUrl":"10.2174/0115734099258183230929173855","url":null,"abstract":"<p><strong>Background: </strong>Research on potential therapeutic targets and new mechanisms of action can greatly improve the efficiency of new drug development.</p><p><strong>Aims: </strong>Polygenic genetic diseases, such as diabetes, are caused by the interaction of multiple gene loci and environmental factors.</p><p><strong>Objectives: </strong>In this study, a disease target identification algorithm based on protein recognition is proposed.</p><p><strong>Materials and methods: </strong>In this method, the related and unrelated targets are collected from literature databases for treating diabetes. The transcribed proteins corresponding to each target are queried in order to construct a protein dataset. Six protein feature extraction algorithms (AAC, CKSAAGP, DDE, DPC, GAAP, and TPC) are utilized to obtain the feature vectors of each protein, which are merged into the full feature vectors.</p><p><strong>Results: </strong>A novel classifier (forgeNet_GPC) based on forgeNet and Gaussian process classifier (GPC) is proposed to classify the proteins.</p><p><strong>Conclusion: </strong>In forgeNet_GPC, forgeNet is utilized to select the important features, and GPC is utilized to solve the classification problem. The experimental results reveal that forgeNet_GPC performs better than 22 classifiers in terms of ROC-AUC, PR-AUC, MCC, Youden Index, and Kappa.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139089708","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> Exploration of a Novel ICMT Inhibitor with More Solubility than Cysmethynil against Membrane Localization of KRAS Mutant in Colorectal Cancer.","authors":"Mohammed Mouhcine, Youness Kadil, Ibtihal Segmani, Imane Rahmoune, Houda Filali","doi":"10.2174/0115734099264451231003172217","DOIUrl":"10.2174/0115734099264451231003172217","url":null,"abstract":"<p><strong>Background: </strong>ICMT (isoprenylcysteine carboxyl methyltransferase) is an enzyme that plays a key role in the post-translational modification of the K-Ras protein. The carboxyl methylation of this protein by ICMT is important for its proper localization and function. Cysmethynil (2-[5-(3-methylphenyl)-l-octyl-lH-indolo-3-yl] acetamide) causes K-Ras mislocalization and interrupts pathways that control cancer cell growth and division through inhibition of ICMT, but its poor water solubility makes it difficult and impractical for clinical use. This indicates that relatively high amounts of cysmethynil would be required to achieve an effective dose, which could result in significant adverse effects in patients.</p><p><strong>Objective: </strong>The general objective of this work was to find virtually new compounds that present high solubility in water and are similar to the pharmacological activity of cysmethynil.</p><p><strong>Materials and methods: </strong>Pharmacophore modeling, pharmacophore-based virtual screening, prediction of ADMET properties (absorption, distribution, metabolism, excretion, and toxicity), and water solubility were performed to recover a water-soluble molecule that shares the same chemical characteristics as cysmethynil using Discovery Studio v16.1.0 (DS16.1), SwissADME server, and pkCSM server.</p><p><strong>Results: </strong>In this study, ten pharmacophore model hypotheses were generated by exploiting the characteristics of cysmethynil. The pharmacophore model validated by the set test method was used to screen the \"Elite Library^®\" and \"Synergy Library\" databases of Asinex. Only 1533 compounds corresponding to all the characteristics of the pharmacophore were retained. Then, the aqueous solubility in water at 25°C of these 1533 compounds was predicted by the Cheng and Merz model. Among these 1533 compounds, two had the optimal water solubility. Finally, the ADMET properties and Log S water solubility by three models (ESOL, Ali, and SILICOS-IT) of the two compounds and cysmethynil were compared, resulting in compound 2 as a potential inhibitor of ICMT.</p><p><strong>Conclusion: </strong>According to the results obtained, the identified compound presented a high solubility in water and could be similar to the pharmacological activity of cysmethynil.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141249064","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> Assessment of Polyherbal Oils as Anti-diabetic Therapeutics.","authors":"Amul S Bahl, Vipin Kumar Verma, Vaishali Prajapati, Jagriti Bhatia, Dharamvir Singh Arya","doi":"10.2174/0115734099267172231012070353","DOIUrl":"10.2174/0115734099267172231012070353","url":null,"abstract":"<p><strong>Background: </strong>Diabetes mellitus (DM) is characterized by elevated blood glucose levels either due to insufficient insulin production, defective insulin action, or both. It affects nearly 537 million individuals worldwide. Pharmacological treatment involves the use of oral antidiabetic agents as mono or combination therapy that effectively aids in controlling hyperglycemia. Despite providing therapeutic benefits, these medications limit their use owing to adverse side effects. Certain natural products, including essential oils, have promising anti-diabetic properties.</p><p><strong>Objective: </strong>The present study explores the effectiveness of two polyherbal oils and their compound towards the treatment of DM based on an <i>In-silico</i> approach to drug investigations Methods: Compounds present in the polyherbal oil formulation were identified using GCMS/ MS analysis. Selected compounds undergo molecular docking with the receptor, and proteins play an important role in DM. The potential compounds showing higher interactions than the known inhibitors or inducers were evaluated using molecular dynamic simulations RMSD value.</p><p><strong>Results: </strong>The compounds identified through GC-MS analysis possess anti-diabetic and antiinflammatory properties. With the aid of <i>in silico</i> prediction methods, compounds such as geraniol, cinnamaldehyde, anethole, caryophyllene, terpinyl acetate, cymene, linalool, menthol, Phenol,2-methoxy-3-(2-propenyl), and 2,6- octadienal,3,7-dimethyl were identified as strong binders of GLUT4 and insulin receptor proteins. Geraniol and Phenol,2-methoxy-3-(2-propenyl) interaction with GLUT4 were of particular importance owing to their conformational stability.</p><p><strong>Conclusion: </strong>Our data suggest an agonistic effect of compounds on target proteins aiding in enhanced insulin activity and could serve as a potential anti-diabetic agent.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49695389","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":"Clodronic Acid has Strong Inhibitory Interactions with the Urease Enzyme of <i>Helicobacter pylori</i>: Computer-aided Design and <i>in vitro</i> Confirmation.","authors":"Mohsen Karami Fath, Saeed Khalili, Masoud Mashhadi Akbar Boojar, Zahra Sadat Hashemi, Mahboubeh Zarei","doi":"10.2174/0115734099271837231026064439","DOIUrl":"10.2174/0115734099271837231026064439","url":null,"abstract":"<p><strong>Background: </strong><i>Helicobacter pylori</i> (HP) infection could lead to various gastrointestinal diseases. Urease is the most important virulence factor of HP. It protects the bacterium against gastric acid.</p><p><strong>Objective: </strong>Therefore, we aimed to design urease inhibitors as drugs against HP infection.</p><p><strong>Methods: </strong>The DrugBank-approved library was assigned with 3D conformations and the structure of the urease was prepared. Using a re-docking strategy, the proper settings were determined for docking by PyRx and GOLD software. Virtual screening was performed to select the best inhibitory drugs based on binding affinity, FitnessScore, and binding orientation to critical amino acids of the active site. The best inhibitory drug was then evaluated by IC₅₀ and the diameter of the zone of inhibition for bacterial growth.</p><p><strong>Results: </strong>The structures of prepared drugs were screened against urease structure using the determined settings. Clodronic acid was determined to be the best-identified drug, due to higher PyRx binding energy, better GOLD FitnessScore, and interaction with critical amino acids of urease. <i>In vitro</i> results were also in line with the computational data. IC₅₀ values of Clodronic acid and Acetohydroxamic Acid (AHA) were 29.78 ± 1.13 and 47.29 ± 2.06 μg/ml, respectively. Diameters of the zones of inhibition were 18 and 15 mm for Clodronic acid and AHA, respectively.</p><p><strong>Conclusion: </strong>Clodronic acid has better HP urease inhibition potential than AHA. Given its approved status, the development of a repurposed drug based on Clodronic acid would require less time and cost. Further, <i>in vivo</i> studies would unveil the efficacy of Clodronic acid as a urease inhibitor.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92158080","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 Bioinformatics Analyses Identify the Core Genes and Pyroptosis-Related Mechanisms of <i>Nardostachys Chinensis</i> for Atrial Fibrillation.","authors":"Weiqi Xue, Yuan Luo, Weifeng He, Mengyuan Yan, Huanyi Zhao, Lijin Qing","doi":"10.2174/0115734099259071231115072421","DOIUrl":"10.2174/0115734099259071231115072421","url":null,"abstract":"<p><strong>Background: </strong><i>Nardostachys chinensis</i> is an herbal medicine widely used in the treatment of atrial fibrillation (AF), but the mechanism is unclear.</p><p><strong>Objective: </strong>To explore the molecular mechanism of <i>N. chinensis</i> against AF.</p><p><strong>Methods: </strong>The TCMSP was used to screen the active <i>N. chinensis</i> compounds and their targets. Differentially expressed genes (DEGs) for AF were identified using open-access databases. Using Venn diagrams, the cross-targets of <i>N. chinensis</i>, pyroptosis, and AF were obtained. The genes underwent molecular docking as well as gene set enrichment analysis (GSEA). A nomogram based on candidate genes was constructed and evaluated with the clinical impact curve. After that, the immune infiltration of the dataset was analyzed by single sample GSEA (ssGSEA). Finally, microRNAs (miRNAs) and transcription factors (TFs) were predicted based on candidate genes.</p><p><strong>Results: </strong>Tumor necrosis factor (TNF) and caspase-8 (CASP8) were obtained as candidate genes by taking the intersection of DEGs, targets of <i>N. chinensis</i>, and pyroptosis-related genes. Tolllike receptor (TLR) and peroxisome proliferator-activated receptor (PPAR) signaling pathways were linked to candidate genes. Additionally, immune cell infiltration analysis revealed that CASP8 was associated with natural killer T cells, natural killer cells, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC), macrophages, CD8 T cells, and CD4 T cells. Finally, miR-34a-5p and several TFs were found to regulate the expression of CASP8 and TNF.</p><p><strong>Conclusion: </strong>CASP8 and TNF are potential targets of <i>N. chinensis</i> intervention in pyroptosisrelated AF, and the TLR/NLRP3 signaling pathway may be associated with this process.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139099418","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, Molecular Docking and Experimental Verification Revealing the Mechanism of Fule Cream against Childhood Atopic Dermatitis.","authors":"Chang Liu, Yuxin Liu, Yi Liu, Jing Guan, Ying Gao, Ling Ou, Yuenan Qi, Xiaoxi Lv, Jianmin Zhang","doi":"10.2174/0115734099257922230925074407","DOIUrl":"10.2174/0115734099257922230925074407","url":null,"abstract":"<p><strong>Background: </strong>The Fule Cream (FLC) is an herbal formula widely used for the treatment of pediatric atopic dermatitis (AD), however, the main active components and functional mechanisms of FLC remain unclear. This study performed an initial exploration of the potential acting mechanisms of FLC in childhood AD treatment through analyses of an AD mouse model using network pharmacology, molecular docking technology, and RNA-seq analysis.</p><p><strong>Materials and methods: </strong>The main bioactive ingredients and potential targets of FLC were collected from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and SwissTargetPrediction databases. An herb-compound-target network was built using Cytoscape 3.7.2. The disease targets of pediatric AD were searched in the DisGeNET, Therapeutic Target Database (TTD), OMIM, DrugBank and GeneCards databases. The overlapping targets between the active compounds and the disease were imported into the STRING database for the construction of the protein-protein interaction (PPI) network. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the intersection targets were performed, and molecular docking verification of the core compounds and targets was then performed using AutoDock Vina 1.1.2. The AD mouse model for experimental verification was induced by MC903.</p><p><strong>Results: </strong>The herb-compound-target network included 415 nodes and 1990 edges. Quercetin, luteolin, beta-sitosterol, wogonin, ursolic acid, apigenin, stigmasterol, kaempferol, sitogluside and myricetin were key nodes. The targets with higher degree values were IL-4, IL-10, IL-1α, IL-1β, TNFα, CXCL8, CCL2, CXCL10, CSF2, and IL-6. GO enrichment and KEGG analyses illustrated that important biological functions involved response to extracellular stimulus, regulation of cell adhesion and migration, inflammatory response, cellular response to cytokine stimulus, and cytokine receptor binding. The signaling pathways in the FLC treatment of pediatric AD mainly involve the PI3K-Akt signaling pathway, cytokine‒cytokine receptor interaction, chemokine signaling pathway, TNF signaling pathway, and NF-κB signaling pathway. The binding energy scores of the compounds and targets indicate a good binding activity. Luteolin, quercetin, and kaempferol showed a strong binding activity with TNFα and IL-4.</p><p><strong>Conclusion: </strong>This study illustrates the main bioactive components and potential mechanisms of FLC in the treatment of childhood AD, and provides a basis and reference for subsequent exploration.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41171971","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":"Rational Design of Dual Inhibitors for Alzheimer's Disease: Insights from Computational Screening of BACE1 and GSK-3β.","authors":"Magham Sai Varshini, Ramakkamma Aishwarya Reddy, Praveen Thaggikuppe Krishnamurthy, Divakar Selvaraj","doi":"10.2174/0115734099270256231018072007","DOIUrl":"10.2174/0115734099270256231018072007","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is one of the most concerned neurodegenerative disorders across the world characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved in AD like Aβ and NFT pathways, are crucial for the development of effective therapeutic strategies. In this study, we aimed to identify and establish promising dual inhibitors targeting BACE1 and GSK-3β, two proteins implicated in Aβ and NFT formation respectively.</p><p><strong>Methods: </strong>We have used molecular docking, ADME property analysis, and MMGBSA calculations for the identification of hit molecules and further evaluation of binding affinity, drug-like properties, and stability against BACE1 and GSK-3β.</p><p><strong>Results: </strong>Our results demonstrated strong binding affinities of ZINC000034853956 towards the active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3β over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3β. Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed in MD simulations support its suitability for further optimization and preclinical studies.</p><p><strong>Conclusion: </strong>Further investigations are warranted to elucidate the precise molecular mechanisms and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration.</p>","PeriodicalId":93961,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71430435","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}