{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T20:44:14Z","timestamp":1763412254756,"version":"3.45.0"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Sirtuin 4 (SIRT4) plays a critical role in regulating oxidative stress, apoptosis, and mitochondrial dysfunction in diabetic nephropathy (DN). This study employed a multi-step in silico strategy to identify novel SIRT4 modulators with potential therapeutic relevance for DN. A ligand-based pharmacophore model was developed using UBCS182, followed by virtual screening of 3,285 compounds from major chemical libraries. Molecular docking revealed strong binding affinities (\u22129.46 to \u22128.41 kcal\/mol), with CSC057320968, PubChem-162316407, and ChemDiv-V013-1548 emerging as top candidates. ADMET analysis confirmed their favorable pharmacokinetic and toxicity profiles. Subsequent 200 ns molecular dynamics simulations demonstrated the stability of protein\u2013ligand complexes, with CSC057320968 exhibiting the most stable interaction profile based on RMSD, RMSF, Rg, and contact frequency analyses. Principal component analysis and free energy landscapes indicated conformational rigidity and energetic favorability for CSC057320968. Density Functional Theory (DFT) analysis further validated its reactivity and chemical softness, supporting its potential as a lead scaffold. This integrated computational pipeline provides novel insights into SIRT4 modulation and offers a rational framework for targeting mitochondrial dysfunction in DN.<\/jats:p>","DOI":"10.1371\/journal.pone.0336948","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T18:26:12Z","timestamp":1763403972000},"page":"e0336948","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational identification of novel SIRT4 inhibitors for diabetic nephropathy using pharmacophore modeling, molecular simulations, and DFT calculations"],"prefix":"10.1371","volume":"20","author":[{"given":"Wenxiang","family":"He","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4818-8754","authenticated-orcid":true,"given":"Jianwu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"pone.0336948.ref001","doi-asserted-by":"crossref","first-page":"1578045","DOI":"10.3389\/fendo.2025.1578045","article-title":"Research on podocyte injury mechanisms in diabetic nephropathy: a bibliometric and knowledge-map analysis from 2000 to 2024","volume":"16","author":"Y Lin","year":"2025","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"16","key":"pone.0336948.ref002","doi-asserted-by":"crossref","first-page":"9035","DOI":"10.3390\/ijms25169035","article-title":"Podocyte Death in Diabetic Kidney Disease: Potential Molecular Mechanisms and Therapeutic Targets","volume":"25","author":"S Zhong","year":"2024","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0336948.ref003","doi-asserted-by":"crossref","first-page":"32","DOI":"10.21608\/rpbs.2025.366022.1363","article-title":"Overview of key molecular processes behind diabetic nephropathy","volume":"9","author":"SM Selim","year":"2025","journal-title":"Records of Pharmaceutical and Biomedical Sciences"},{"issue":"1","key":"pone.0336948.ref004","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13098-025-01655-2","article-title":"Recent advances in understanding the mechanisms by which sodium-glucose co-transporter type 2 inhibitors protect podocytes in diabetic nephropathy","volume":"17","author":"X Chen","year":"2025","journal-title":"Diabetol Metab Syndr"},{"issue":"7","key":"pone.0336948.ref005","doi-asserted-by":"crossref","first-page":"3330","DOI":"10.3390\/ijms26073330","article-title":"Comprehending the Role of Metabolic and Hemodynamic Factors Alongside Different Signaling Pathways in the Pathogenesis of Diabetic Nephropathy","volume":"26","author":"Y Ratan","year":"2025","journal-title":"Int J Mol Sci"},{"key":"pone.0336948.ref006","article-title":"Retracted SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis","author":"J-X Shi","year":"2024","journal-title":"DA Spandidos"},{"issue":"2","key":"pone.0336948.ref007","doi-asserted-by":"crossref","first-page":"112863","DOI":"10.1016\/j.yexcr.2021.112863","article-title":"FOXM1-activated SIRT4 inhibits NF-\u03baB signaling and NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in diabetic nephropathy","volume":"408","author":"X Xu","year":"2021","journal-title":"Exp Cell Res"},{"key":"pone.0336948.ref008","doi-asserted-by":"crossref","first-page":"901066","DOI":"10.3389\/fendo.2022.901066","article-title":"Sirtuin Family and Diabetic Kidney Disease","volume":"13","author":"C Bian","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"5","key":"pone.0336948.ref009","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1021\/acs.jproteome.9b00086","article-title":"Mitochondrial Function, Metabolic Regulation, and Human Disease Viewed through the Prism of Sirtuin 4 (SIRT4) Functions","volume":"18","author":"CN Betsinger","year":"2019","journal-title":"J Proteome Res"},{"issue":"6","key":"pone.0336948.ref010","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.chembiol.2017.06.002","article-title":"SIRT4 Is a Regulator of Insulin Secretion","volume":"24","author":"E Zaganjor","year":"2017","journal-title":"Cell Chem Biol"},{"key":"pone.0336948.ref011","doi-asserted-by":"crossref","first-page":"783","DOI":"10.3389\/fendo.2018.00783","article-title":"The Roles of Mitochondrial SIRT4 in Cellular Metabolism","volume":"9","author":"Z Min","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"3","key":"pone.0336948.ref012","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s12012-014-9287-6","article-title":"SIRT4 Suppresses Inflammatory Responses in Human Umbilical Vein Endothelial Cells","volume":"15","author":"Y Tao","year":"2015","journal-title":"Cardiovasc Toxicol"},{"issue":"4","key":"pone.0336948.ref013","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1038\/ki.2015.250","article-title":"Relevance of TNF-\u03b1 in the context of other inflammatory cytokines in the progression of diabetic nephropathy","volume":"88","author":"L Sun","year":"2015","journal-title":"Kidney Int"},{"key":"pone.0336948.ref014","doi-asserted-by":"crossref","first-page":"115499","DOI":"10.1016\/j.biopha.2023.115499","article-title":"Therapeutic application of traditional Chinese medicine in kidney disease: Sirtuins as potential targets","volume":"167","author":"Q Jin","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"pone.0336948.ref015","doi-asserted-by":"crossref","first-page":"113620","DOI":"10.1016\/j.biopha.2022.113620","article-title":"Sirtuins as novel pharmacological targets in podocyte injury and related glomerular diseases","volume":"155","author":"T Liu","year":"2022","journal-title":"Biomed Pharmacother"},{"issue":"3","key":"pone.0336948.ref016","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1021\/acs.jmedchem.3c01496","article-title":"Specific Inhibitors of Mitochondrial Deacylase Sirtuin 4 Endowed with Cellular Activity","volume":"67","author":"M Pannek","year":"2024","journal-title":"J Med Chem"},{"key":"pone.0336948.ref017","volume-title":"LigPrep","author":"LigPrep","year":"2018"},{"key":"pone.0336948.ref018","author":"LJSS Schr\u00f6dinger","year":"2017"},{"issue":"3","key":"pone.0336948.ref019","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s10822-013-9643-9","article-title":"Effects of histidine protonation and rotameric states on virtual screening of M. tuberculosis RmlC","volume":"27","author":"MO Kim","year":"2013","journal-title":"J Comput Aided Mol Des"},{"key":"pone.0336948.ref020","doi-asserted-by":"crossref","unstructured":"Jeong SW, et al. Prediction of enthalpy of vaporization for particulate matter through molecular dynamics using OPLS force field. 2025;:106595.","DOI":"10.1016\/j.jaerosci.2025.106595"},{"issue":"7","key":"pone.0336948.ref021","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"RA Friesner","year":"2004","journal-title":"J Med Chem"},{"key":"pone.0336948.ref022","volume-title":"Discovery Studio Visualizer","author":"i Visualizer DJA s","year":"2005"},{"issue":"5","key":"pone.0336948.ref023","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1093\/bib\/bbz103","article-title":"Computational\/in silico methods in drug target and lead prediction","volume":"21","author":"FE Agamah","year":"2020","journal-title":"Brief Bioinform"},{"key":"pone.0336948.ref024","doi-asserted-by":"crossref","unstructured":"Ejeh S, et al. In silico design and pharmacokinetics investigation of some novel hepatitis C virus NS5B inhibitors: pharmacoinformatics approach. 2022;46(1):1\u201311.","DOI":"10.1186\/s42269-022-00796-y"},{"key":"pone.0336948.ref025","doi-asserted-by":"crossref","unstructured":"Bowers KJ, et al. Scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proceedings of the 2006 ACM\/IEEE Conference on Supercomputing, 2006.","DOI":"10.1145\/1188455.1188544"},{"issue":"20","key":"pone.0336948.ref026","doi-asserted-by":"crossref","first-page":"10096","DOI":"10.1063\/1.1808117","article-title":"A modified TIP3P water potential for simulation with Ewald summation","volume":"121","author":"DJ Price","year":"2004","journal-title":"J Chem Phys"},{"issue":"6","key":"pone.0336948.ref027","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1080\/0026897021000044025","article-title":"Constant pressure-constant temperature molecular dynamics: a correct constrained NPT ensemble using the molecular virial","volume":"101","author":"G Kalibaeva","year":"2003","journal-title":"Molecular Physics"},{"key":"pone.0336948.ref028","volume-title":"Gaussian 09W Reference","author":"A Frisch","year":"2009"},{"issue":"3","key":"pone.0336948.ref029","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1080\/07391102.2021.2015446","article-title":"Computational investigation of potent inhibitors against YsxC: structure-based pharmacophore modeling, molecular docking, molecular dynamics, and binding free energy","volume":"41","author":"R Kumari","year":"2023","journal-title":"J Biomol Struct Dyn"},{"issue":"15","key":"pone.0336948.ref030","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.1080\/07391102.2017.1404935","article-title":"In-Silico molecular docking and simulation studies on novel chalcone and flavone hybrid derivatives with 1, 2, 3-triazole linkage as vital inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase","volume":"36","author":"M Thillainayagam","year":"2018","journal-title":"J Biomol Struct Dyn"},{"issue":"1","key":"pone.0336948.ref031","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.jsps.2015.02.008","article-title":"Synthesis, molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents","volume":"24","author":"A Husain","year":"2016","journal-title":"Saudi Pharm J"},{"issue":"3","key":"pone.0336948.ref032","article-title":"In silico study, synthesis, and evaluation of the antimalarial activity of hybrid dimethoxy pyrazole 1, 3, 5\u2010triazine derivatives","volume":"35","author":"P Gogoi","year":"2021","journal-title":"Eur J Med Chem"},{"issue":"1","key":"pone.0336948.ref033","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s11030-018-9867-7","article-title":"Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their \u03b2-adrenoceptor blocking property","volume":"23","author":"S Behrouz","year":"2019","journal-title":"Mol Divers"},{"issue":"4","key":"pone.0336948.ref034","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1021\/acs.jctc.7b00028","article-title":"How Molecular Size Impacts RMSD Applications in Molecular Dynamics Simulations","volume":"13","author":"K Sargsyan","year":"2017","journal-title":"J Chem Theory Comput"},{"issue":"3","key":"pone.0336948.ref035","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0119264","article-title":"Automatic identification of mobile and rigid substructures in molecular dynamics simulations and fractional structural fluctuation analysis","volume":"10","author":"L Mart\u00ednez","year":"2015","journal-title":"PLoS One"},{"issue":"7","key":"pone.0336948.ref036","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1042\/CS20210625","article-title":"Mechanisms of podocyte injury and implications for diabetic nephropathy","volume":"136","author":"F Barutta","year":"2022","journal-title":"Clin Sci (Lond)"},{"key":"pone.0336948.ref037","first-page":"3","article-title":"Diabetic nephropathy: an overview","volume-title":"Diabetic nephropathy: methods and protocols","author":"MK Sagoo","year":"2019"},{"issue":"1","key":"pone.0336948.ref038","doi-asserted-by":"crossref","first-page":"342","DOI":"10.3892\/etm.2016.3938","article-title":"SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis","volume":"13","author":"J-X Shi","year":"2017","journal-title":"Exp Ther Med"},{"issue":"7","key":"pone.0336948.ref039","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1016\/j.cell.2014.11.046","article-title":"Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity","volume":"159","author":"RA Mathias","year":"2014","journal-title":"Cell"},{"key":"pone.0336948.ref040","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13148-016-0224-3","article-title":"Sirtuin functions and modulation: from chemistry to the clinic","volume":"8","author":"V Carafa","year":"2016","journal-title":"Clin Epigenetics"},{"key":"pone.0336948.ref041","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.3389\/fphar.2019.01270","article-title":"SIRT6 Inhibitor, OSS_128167 Restricts Hepatitis B Virus Transcription and Replication Through Targeting Transcription Factor Peroxisome Proliferator-Activated Receptors \u03b1","volume":"10","author":"H Jiang","year":"2019","journal-title":"Front Pharmacol"},{"issue":"5","key":"pone.0336948.ref042","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.cell.2006.06.057","article-title":"SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells","volume":"126","author":"MC Haigis","year":"2006","journal-title":"Cell"},{"issue":"7","key":"pone.0336948.ref043","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/aps.2012.21","article-title":"Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors","volume":"33","author":"S Sakkiah","year":"2012","journal-title":"Acta Pharmacol Sin"},{"key":"pone.0336948.ref044","article-title":"2D-QSAR and Molecular Docking based Virtual Screening of the Herbal Molecules Against Alzheimer\u2019s Disorder: An Approach to Predict CNS Activity","author":"A Thakur","year":"2022","journal-title":"bioRxiv"},{"issue":"2","key":"pone.0336948.ref045","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1021\/acs.jcim.8b00545","article-title":"Comparative Assessment of Scoring Functions: The CASF-2016 Update","volume":"59","author":"M Su","year":"2019","journal-title":"J Chem Inf Model"},{"issue":"4","key":"pone.0336948.ref046","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1021\/acs.jctc.7b00028","article-title":"How Molecular Size Impacts RMSD Applications in Molecular Dynamics Simulations","volume":"13","author":"K Sargsyan","year":"2017","journal-title":"J Chem Theory Comput"},{"issue":"9","key":"pone.0336948.ref047","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1021\/acs.jmedchem.5b01684","article-title":"Role of Molecular Dynamics and Related Methods in Drug Discovery","volume":"59","author":"M De Vivo","year":"2016","journal-title":"J Med Chem"},{"issue":"5","key":"pone.0336948.ref048","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1093\/bib\/bbz103","article-title":"Computational\/in silico methods in drug target and lead prediction","volume":"21","author":"FE Agamah","year":"2020","journal-title":"Brief Bioinform"},{"issue":"1","key":"pone.0336948.ref049","doi-asserted-by":"crossref","DOI":"10.1186\/s42269-022-00796-y","article-title":"In silico design and pharmacokinetics investigation of some novel hepatitis C virus NS5B inhibitors: pharmacoinformatics approach","volume":"46","author":"S Ejeh","year":"2022","journal-title":"Bull Natl Res Cent"},{"key":"pone.0336948.ref050","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"CA Lipinski","year":"2001","journal-title":"Adv Drug Deliv Rev"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0336948","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T18:26:22Z","timestamp":1763403982000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0336948"}},"subtitle":[],"editor":[{"given":"Joazaizulfazli","family":"Jamalis","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":50,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0336948","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]}}}