{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:51:50Z","timestamp":1791474710994,"version":"4.3.4"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007224","name":"National Foundation for Science and Technology Development","doi-asserted-by":"publisher","award":["106-YS.01-2015.12"],"award-info":[{"award-number":["106-YS.01-2015.12"]}],"id":[{"id":"10.13039\/100007224","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>In the present study, <jats:italic>in silico<\/jats:italic> predictions and molecular docking were performed on five clerodane diterpenes <jats:bold>(1\u20135)<\/jats:bold> from <jats:italic>Polyalthia longifolia<\/jats:italic> seeds to evaluate their potential as xanthine oxidase (XO) inhibitors. The initial screening was conducted by target prediction using TargetNet web server application and only compounds <jats:bold>3<\/jats:bold> and <jats:bold>4<\/jats:bold> showed a potential interaction with XO. Compounds 3 and 4 were subsequently subjected to <jats:italic>in silico<\/jats:italic> analyses on XO protein structure (PDB: 1N5X) using Schr\u00f6dinger Release 2020\u20133 followed by structural modeling &amp; molecular simulation studies to confirm the initial prediction result and identify the binding mode of these compounds to the XO. Molecular docking results revealed that compounds 3 (-37.3 kcal\/mol) and 4 (-32.0 kcal\/mol) binds more stably to XO than the reference drug allopurinol (-27.0 kcal\/mol). Interestingly, two residues Glu 802 and Thr 1010 were observed as the two main H-bond binding sites for both tested compounds and the allopurinol. The center scaffold of allopurinol was positioned by some \u03c0-\u03c0 stacking with Phe 914 and Phe 1009, while that of compounds <jats:bold>3<\/jats:bold> and <jats:bold>4<\/jats:bold> were supported by many hydrophobic interactions mainly with Leu 648, Phe 649, Phe 1013, and Leu 1014. Additionally, the docking simulation predicted that the inhibitory effect of compounds <jats:bold>3<\/jats:bold> and <jats:bold>4<\/jats:bold> was mediated by creating H-bond with particularly Glu 802, which is a key amino acid for XO enzyme inhibition. Altogether, <jats:italic>in vitro<\/jats:italic> studies showed that compounds <jats:bold>3<\/jats:bold> and <jats:bold>4<\/jats:bold> had better inhibitory capacity against XO enzyme with IC<jats:sub>50<\/jats:sub> values significantly (<jats:italic>p<\/jats:italic> &lt; 0.001) lower than that of allopurinol. In short, the present study identified cleroda-4(18),13-dien-15,16-olide as novel potential XO inhibitors, which can be potentially used for the treatment of gout.<\/jats:p>","DOI":"10.1371\/journal.pone.0253572","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T17:38:39Z","timestamp":1625074719000},"page":"e0253572","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cleroda-4(18),13-dien-15,16-olide as novel xanthine oxidase inhibitors: An integrated in silico and in vitro study"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9222-632X","authenticated-orcid":true,"given":"Ha Thi","family":"Nguyen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thien-Y","family":"Vu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tikam 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Scand"},{"issue":"4","key":"pone.0253572.ref002","doi-asserted-by":"crossref","first-page":"3766","DOI":"10.1016\/j.foodchem.2013.06.092","article-title":"Effect of luteolin on xanthine oxidase: Inhibition kinetics and interaction mechanism merging with docking simulation","volume":"141","author":"J Yan","year":"2013","journal-title":"Food Chem"},{"key":"pone.0253572.ref003","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.ejmech.2017.11.071","article-title":"Xanthine oxidase inhibitory activity of natural and hemisynthetic flavonoids from Gardenia oudiepe (Rubiaceae) in vitro and molecular docking studies","volume":"143","author":"MD Santi","year":"2018","journal-title":"Eur J Med Chem"},{"issue":"4","key":"pone.0253572.ref004","first-page":"925","article-title":"Gout and hyperuricemia","volume":"59","author":"MD Harris","year":"1999","journal-title":"Am Fam Physician"},{"key":"pone.0253572.ref005","first-page":"233","article-title":"Epidemiology of gout","volume":"12","author":"E Roddy","year":"2010","journal-title":"Arthritis Res The"},{"issue":"2","key":"pone.0253572.ref006","first-page":"71","article-title":"Inouye college of pharmacy scripts: Perspectives on the epidemiology of gout and hyperuricemia","volume":"78","author":"YM Roman","year":"2019","journal-title":"Hawaii J Med Public Health"},{"issue":"2","key":"pone.0253572.ref007","doi-asserted-by":"crossref","first-page":"128","DOI":"10.12691\/ajnr-7-2-4","article-title":"Factors affecting quality of life and work productivity among patients with gout","volume":"7","author":"MM Ali","year":"2019","journal-title":"Am J Nurs Res"},{"issue":"1","key":"pone.0253572.ref008","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3233\/THC-191951","article-title":"Treat-to-target urate-lowering therapy in primary gout patients: A real-world retrospective study at a dedicated gout clinic in China","volume":"29","author":"X-S Bai","year":"2020","journal-title":"Technol Heal Care"},{"key":"pone.0253572.ref009","doi-asserted-by":"crossref","first-page":"680853","DOI":"10.1155\/2015\/680853","article-title":"Increased risk of cancer in relation to gout: a review of three prospective cohort studies with 50,358 subjects","volume":"2015","author":"W Wang","year":"2015","journal-title":"Mediators Inflamm"},{"issue":"6","key":"pone.0253572.ref010","doi-asserted-by":"crossref","first-page":"787","DOI":"10.4239\/wjd.v5.i6.787","article-title":"Linking uric acid metabolism to diabetic complications","volume":"5","author":"A Kushiyama","year":"2014","journal-title":"World J Diabetes"},{"issue":"12","key":"pone.0253572.ref011","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1158\/1541-7786.MCR-08-0012","article-title":"Anti-gout agent allopurinol exerts cytotoxicity to human hormone-refractory prostate cancer cells in combination with tumor necrosis factor-related apoptosis-inducing ligand","volume":"6","author":"T Yasuda","year":"2008","journal-title":"Mol Cancer Res"},{"issue":"8","key":"pone.0253572.ref012","doi-asserted-by":"crossref","first-page":"623","DOI":"10.2165\/00003088-200746080-00001","article-title":"Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol","volume":"46","author":"RO Day","year":"2007","journal-title":"Clinical Pharmacokinetics"},{"issue":"3","key":"pone.0253572.ref013","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s11418-009-0331-y","article-title":"Hydroxychavicol: A potent xanthine oxidase inhibitor obtained from the leaves of betel, Piper betle","volume":"63","author":"K Murata","year":"2009","journal-title":"J Nat Med"},{"issue":"4","key":"pone.0253572.ref014","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/0891-5849(95)02056-X","article-title":"Allopurinol, an inhibitor of xanthine oxidase, reduces uric acid levels and modifies the signs associated with copper deficiency in rats fed fructose","volume":"20","author":"M Fields","year":"1996","journal-title":"Free Radic Biol Med"},{"key":"pone.0253572.ref015","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s11255-011-9929-6","article-title":"Allopurinol, uric acid, and oxidative stress in cardiorenal disease","volume":"43","author":"M Riegersperger","year":"2011","journal-title":"Int Urol Nephrol"},{"key":"pone.0253572.ref016","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.ejmech.2014.01.058","article-title":"Design, synthesis and molecular modeling of aloe-emodin derivatives as potent xanthine oxidase inhibitors","volume":"75","author":"D-H Shi","year":"2014","journal-title":"Eur J Med Chem"},{"issue":"21","key":"pone.0253572.ref017","doi-asserted-by":"crossref","first-page":"5990","DOI":"10.1016\/j.bmcl.2009.09.076","article-title":"Insights into the inhibition of xanthine oxidase by curcumin","volume":"19","author":"L Shen","year":"2009","journal-title":"Bioorganic Med Chem Lett"},{"issue":"6","key":"pone.0253572.ref018","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.bcp.2007.11.023","article-title":"Structure-activity relationship of coumarin derivatives on xanthine oxidase-inhibiting and free radical-scavenging activities","volume":"75","author":"HC Lin","year":"2008","journal-title":"Biochem Pharmacol"},{"issue":"15","key":"pone.0253572.ref019","doi-asserted-by":"crossref","first-page":"3602","DOI":"10.1016\/j.bmcl.2017.01.053","article-title":"Synthesis and evaluation of hydroxychalcones as multifunctional non-purine xanthine oxidase inhibitors for the treatment of hyperuricemia","volume":"27","author":"Z Xie","year":"2017","journal-title":"Bioorganic Med Chem Lett"},{"issue":"4","key":"pone.0253572.ref020","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.bionut.2014.07.005","article-title":"Isolation of a bioactive flavonoid from Spilanthes calva D.C. in vitro xanthine oxidase assay and in silico study","volume":"4","author":"P Jayaraj","year":"2014","journal-title":"Biomed Prev Nutr"},{"issue":"3","key":"pone.0253572.ref021","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1074\/jbc.M208307200","article-title":"An extremely potent inhibitor of xanthine oxidoreductase: Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition","volume":"278","author":"K Okamoto","year":"2003","journal-title":"J Biol Chem"},{"issue":"2\u20133","key":"pone.0253572.ref022","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.jep.2004.04.012","article-title":"Xanthine oxidase inhibitors from the leaves of Lagerstroemia speciosa (L.) Pers","volume":"93","author":"T Unno","year":"2004","journal-title":"J Ethnopharmacol"},{"issue":"2","key":"pone.0253572.ref023","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.bmcl.2013.12.031","article-title":"Microwave assisted synthesis of naphthopyrans catalysed by silica supported fluoroboric acid as a new class of non purine xanthine oxidase inhibitors","volume":"24","author":"S Sharma","year":"2014","journal-title":"Bioorganic Med Chem Lett"},{"key":"pone.0253572.ref024","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.phytol.2015.03.005","article-title":"Xanthine oxidase inhibitors isolated from Piper nudibaccatum","volume":"12","author":"HX Liu","year":"2015","journal-title":"Phytochem Lett"},{"issue":"04","key":"pone.0253572.ref025","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1055\/s-2006-961481","article-title":"Activity of polyphenolic crude extracts as scavengers of superoxide radicals and inhibitors of xanthine oxidase","volume":"58","author":"L Costantino","year":"1992","journal-title":"Planta Med"},{"issue":"1","key":"pone.0253572.ref026","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.saa.2008.09.021","article-title":"Fluorescence quenching study of quercetin interaction with bovine milk xanthine oxidase","volume":"72","author":"F Rasoulzadeh","year":"2009","journal-title":"Spectrochim Acta\u2014Part A Mol Biomol Spectrosc"},{"issue":"3","key":"pone.0253572.ref027","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.foodchem.2012.05.049","article-title":"The influence of flavonoids on the binding of pantoprazole to bovine serum albumin by spectroscopic methods: With the viewpoint of food\/drug interference","volume":"135","author":"S Shi","year":"2012","journal-title":"Food Chem"},{"key":"pone.0253572.ref028","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1021\/np970237h","article-title":"Structure\u2212Activity Relationship and Classification of Flavonoids as Inhibitors of Xanthine Oxidase and Superoxide Scavengers","volume":"61","author":"P Cos","year":"1998","journal-title":"J Nat Prod"},{"key":"pone.0253572.ref029","doi-asserted-by":"crossref","first-page":"15965","DOI":"10.1038\/s41598-020-72840-8","article-title":"Dual COX and 5-LOX inhibition by clerodane diterpenes from seeds of Polyalthia longifolia (Sonn.) Thwaites","volume":"10","author":"HT Nguyen","year":"2020","journal-title":"Sci Rep"},{"key":"pone.0253572.ref030","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s10822-016-9915-2","article-title":"TargetNet: a web service for predicting potential drug\u2013target interaction profiling via multi-target SAR models","volume":"30","author":"ZJ Yao","year":"2016","journal-title":"J Comput Aided Mol Des"},{"key":"pone.0253572.ref031","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nbt1284","article-title":"Relating protein pharmacology by ligand chemistry","volume":"25","author":"MJ Keiser","year":"2007","journal-title":"Nat Biotechnol"},{"issue":"10","key":"pone.0253572.ref032","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1002\/prot.23106","article-title":"The VSGB 2.0 model: A next generation energy model for high resolution protein structure modeling","volume":"79","author":"J Li","year":"2011","journal-title":"Proteins Struct Funct Bioinforma"},{"issue":"3","key":"pone.0253572.ref033","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"GM Sastry","year":"2013","journal-title":"J Comput Aided Mol Des"},{"issue":"21","key":"pone.0253572.ref034","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes","volume":"49","author":"RA Friesner","year":"2006","journal-title":"J Med Chem"},{"issue":"1","key":"pone.0253572.ref035","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1021\/ci300425v","article-title":"MM\/GBSA binding energy prediction on the PDBbind data set: Successes, failures, and directions for further improvement","volume":"53","author":"PA Greenidge","year":"2013","journal-title":"J Chem Inf Model"},{"key":"pone.0253572.ref036","doi-asserted-by":"crossref","unstructured":"Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, et al. Scalable algorithms for molecular dynamics simulations on commodity clusters. Proceedings of the 2006 ACM\/IEEE Conference on Supercomputing, SC\u201906. 2006:43. doi: 10.1145\/1188455.1188544","DOI":"10.1145\/1188455.1188544"},{"key":"pone.0253572.ref037","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s43094-020-00028-y","article-title":"In vitro antioxidant, anti-inflammatory, and anticancer activities of methanolic extract and its metabolites of whole plant Cardiospermum canescens Wall","volume":"6","author":"A Ketha","year":"2020","journal-title":"Futur J Pharm Sci"},{"issue":"13","key":"pone.0253572.ref038","doi-asserted-by":"crossref","first-page":"3278","DOI":"10.1111\/j.1742-4658.2008.06489.x","article-title":"Mammalian xanthine oxidoreductase\u2014Mechanism of transition from xanthine dehydrogenase to xanthine oxidase","volume":"275","author":"T Nishino","year":"2008","journal-title":"FEBS Journal"},{"issue":"13","key":"pone.0253572.ref039","doi-asserted-by":"crossref","first-page":"8760","DOI":"10.1074\/jbc.M804517200","article-title":"Substrate orientation and catalysis at the molybdenum site in xanthine oxidase: Crystal structures in complex with xanthine and lumazine","volume":"284","author":"JM Pauff","year":"2009","journal-title":"J Biol Chem"},{"issue":"4","key":"pone.0253572.ref040","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1093\/jb\/mvm053","article-title":"Human xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site: Roles of active site residues in binding and activation of purine substrate","volume":"141","author":"Y Yamaguchi","year":"2007","journal-title":"J Biochem"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0253572","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T17:39:18Z","timestamp":1625074758000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0253572"}},"subtitle":[],"editor":[{"given":"Parag A.","family":"Deshpande","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,6,30]]},"references-count":40,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0253572","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,30]]}}}