{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T07:28:28Z","timestamp":1772350108470,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004508","name":"Prince of Songkla University","doi-asserted-by":"crossref","award":["REV65029"],"award-info":[{"award-number":["REV65029"]}],"id":[{"id":"10.13039\/501100004508","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Malaria is a major global health concern caused by Plasmodium parasites, among which Plasmodium falciparum is responsible for the most severe and fatal cases. The emergence of drug resistance to existing antimalarial therapies necessitates the discovery of novel molecular targets and chemically distinct inhibitors. Current study employed an integrated in silico drug discovery pipeline combining high-throughput structure-based virtual screening of 1549 deep-sea marine microbial metabolites with MM-GBSA binding free-energy estimation, QikProp-based ADME\/Tox profiling, and 100 ns molecular dynamics (MD) simulations to link rapid screening with dynamic verification of binding stability. Molecular docking against Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH; PDB ID: 7KZ4) yielded five top-ranked compounds with Glide scores ranging from \u221212.02 to \u221210.61 kcal\u00b7mol\u22121, which is higher than the Primaquine (\u22126.920 kcal\u00b7mol\u22121; a clinically approved antimalarial reference compound). MM-GBSA analysis further refined hit selection, producing binding free energies (\u0394G_bind) between \u221263.28 and \u221231.37 kcal\u00b7mol\u22121. The selected lead compounds included (\u00b1)-puniceusine P, aspergilol F, tersaphilone C, 4-carbglyceryl-3,3\u2032-dihydroxy-5,5\u2032-dimethyldiphenyl ether, and 15-O-methyl ML-236A. The top hits were subjected to 100 ns MD simulations in Desmond, demonstrating stable protein\u2013ligand complexes, particularly for (\u00b1)-puniceusine P and 15-O-methyl ML-236A (protein backbone root mean square deviation (RMSD; ~0.8\u20131.0 \u00c5). ADME profiling indicated acceptable predicted physicochemical and pharmacokinetic properties. Overall, these in silico findings highlight deep-sea marine microbial metabolites as promising PfDHODH inhibitor candidates requiring experimental validation.<\/jats:p>","DOI":"10.3390\/biology15050392","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T17:05:16Z","timestamp":1772211916000},"page":"392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure-Based Screening of Deep-Sea Microbial Metabolites Against Plasmodium falciparum Dihydroorotate Dehydrogenase"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5184-9085","authenticated-orcid":false,"given":"Avtar","family":"Singh","sequence":"first","affiliation":[{"name":"International Centre of Excellence in Seafood Science and Innovation, Faculty of Agro-Industry, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7205-7389","authenticated-orcid":false,"given":"Kannan R. R.","family":"Rengasamy","sequence":"additional","affiliation":[{"name":"International Centre of Excellence in Seafood Science and Innovation, Faculty of Agro-Industry, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand"},{"name":"Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9433-3671","authenticated-orcid":false,"given":"Soottawat","family":"Benjakul","sequence":"additional","affiliation":[{"name":"International Centre of Excellence in Seafood Science and Innovation, Faculty of Agro-Industry, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand"},{"name":"Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.5603\/IMH.2022.0006","article-title":"Challenges in the diagnosis and treatment of malaria in Polish workers returning from Africa: A case series and review of literature","volume":"73","author":"Kulawiak","year":"2022","journal-title":"Int. Marit. Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1365-3024.2011.01340.x","article-title":"Genomics and integrated systems biology in Plasmodium falciparum: A path to malaria control and eradication","volume":"34","author":"Chung","year":"2012","journal-title":"Parasite Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e113","DOI":"10.4172\/2155-9597.1000e113","article-title":"Human and mosquito lysozymes in malaria: Old molecules for new approaches towards diagnosis, therapy and vector control","volume":"3","author":"Prato","year":"2012","journal-title":"J. Bacteriol. Parasitol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s12936-022-04115-8","article-title":"Malaria chemoprevention and drug resistance: A review of the literature and policy implications","volume":"21","author":"Plowe","year":"2022","journal-title":"Malar. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1146\/annurev-micro-020518-115546","article-title":"Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria","volume":"74","author":"Wicht","year":"2020","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tang, L., Wang, Y., Gong, X., Xiang, J., Zhang, Y., Xiang, Q., and Li, J. (2023). Integrated transcriptome and metabolome analysis to investigate the mechanism of intranasal insulin treatment in a rat model of vascular dementia. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1182803"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13020-023-00745-5","article-title":"A novel microbial and hepatic biotransformation-integrated network pharmacology strategy explores the therapeutic mechanisms of bioactive herbal products in neurological diseases: The effects of Astragaloside IV on intracerebral hemorrhage as an example","volume":"18","author":"Hu","year":"2023","journal-title":"Chin. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Tan, Q., Chu, H., Wei, J., Yan, S., Sun, X., Wang, J., Zhu, L., and Yang, F. (2024). Astaxanthin Alleviates Hepatic Lipid Metabolic Dysregulation Induced by Microcystin-LR. Toxins, 16.","DOI":"10.3390\/toxins16090401"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.jiph.2023.04.014","article-title":"Efficacy and mortality of ceftazidime\/avibactam-based regimens in carbapenem-resistant Gram-negative bacteria infections: A retrospective multicenter observational study","volume":"16","author":"Zhuang","year":"2023","journal-title":"J. Infect. Public Health"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s15010-024-02324-8","article-title":"Ceftazidime\/avibactam versus polymyxin B in carbapenem-resistant Klebsiella pneumoniae infections: A propensity score-matched multicenter real-world study","volume":"53","author":"Zhuang","year":"2025","journal-title":"Infection"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s13258-023-01394-6","article-title":"QTL mapping and identification of candidate genes for cold tolerance at the germination stage in wild rice","volume":"45","author":"Pan","year":"2023","journal-title":"Genes Genom."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.4155\/fmc-2017-0250","article-title":"Plasmodium Falciparum Dihydroorotate Dehydrogenase: A Drug Target against Malaria","volume":"10","author":"Hoelz","year":"2018","journal-title":"Future Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"226","DOI":"10.2174\/187152610791163336","article-title":"Plasmodium dihydroorotate dehydrogenase: A promising target for novel anti-malarial chemotherapy","volume":"10","author":"Phillips","year":"2010","journal-title":"Infect. Disord. Drug Targets"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17980","DOI":"10.1074\/jbc.M114.558353","article-title":"In vitro resistance selections for Plasmodium falciparum dihydroorotate dehydrogenase inhibitors give mutants with multiple point mutations in the drug-binding site and altered growth","volume":"289","author":"Ross","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5540","DOI":"10.1021\/jm200592f","article-title":"Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential","volume":"54","author":"Coteron","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"296ra111","DOI":"10.1126\/scitranslmed.aaa6645","article-title":"A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria","volume":"7","author":"Phillips","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/S1473-3099(18)30309-8","article-title":"Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: A proof-of-concept, open-label, phase 2a study","volume":"18","author":"Casapia","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eaav1636","DOI":"10.1126\/scitranslmed.aav1636","article-title":"In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model","volume":"11","author":"Mandt","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1080\/13543776.2023.2280596","article-title":"Recent advances on patents of Plasmodium falciparum dihydroorotate dehydrogenase (Pf DHODH) inhibitors as antimalarial agents","volume":"33","author":"Gehlot","year":"2023","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Barzkar, N., Sukhikh, S., and Babich, O. (2024). Study of marine microorganism metabolites: New resources for bioactive natural products. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1285902"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"108521","DOI":"10.1016\/j.bioorg.2025.108521","article-title":"Exploring the bioactive potential of deep-sea microorganisms: A review of recent discoveries","volume":"161","author":"Khan","year":"2025","journal-title":"Bioorg. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3390\/md7020130","article-title":"Marine Antimalarials","volume":"7","author":"Fattorusso","year":"2009","journal-title":"Mar. Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7397","DOI":"10.1016\/S0040-4020(02)00825-6","article-title":"12,34-Oxamanzamines, novel biocatalytic and natural products from manzamine producing Indo-Pacific sponges","volume":"58","author":"Yousaf","year":"2002","journal-title":"Tetrahedron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6282","DOI":"10.1016\/j.tetlet.2008.08.052","article-title":"A new antimalarial polyether from a marine Streptomyces sp. H668","volume":"49","author":"Na","year":"2008","journal-title":"Tetrahedron Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4436","DOI":"10.1039\/D2RA07977A","article-title":"Marine organisms as potential sources of natural products for the prevention and treatment of malaria","volume":"13","author":"Negm","year":"2023","journal-title":"RSC Adv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.2174\/1568026614666140929124445","article-title":"Structure-based virtual screening for drug discovery: Principles, applications and recent advances","volume":"14","author":"Lionta","year":"2014","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nrd1549","article-title":"Docking and scoring in virtual screening for drug discovery: Methods and applications","volume":"3","author":"Kitchen","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1007\/s00044-016-1591-1","article-title":"Identification of novel natural compound inhibitors for human complement component 5a receptor by homology modeling and virtual screening","volume":"25","author":"Shaikh","year":"2016","journal-title":"Med. Chem. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s43088-020-00059-7","article-title":"In silico molecular docking studies and MM\/GBSA analysis of coumarin-carbonodithioate hybrid derivatives divulge the anticancer potential against breast cancer","volume":"9","author":"Pattar","year":"2020","journal-title":"Beni Suef Univ. J. Basic Appl. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Vittorio, S., Gitto, R., Adornato, I., Russo, E., and De Luca, L. (2021). In silico strategy for targeting the mTOR kinase at rapamycin binding site by small molecules. Molecules, 26.","DOI":"10.3390\/molecules26041103"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/157340911795677602","article-title":"Molecular docking: A powerful approach for structure-based drug discovery","volume":"7","author":"Meng","year":"2011","journal-title":"Curr. Comput. Aided Drug Des."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Remtulla, R., Das, S.K., and Levin, L.A. (2021). Predicting absorption-distribution properties of neuroprotective phosphine-borane compounds using in silico modeling and machine learning. Molecules, 26.","DOI":"10.3390\/molecules26092505"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1021\/acsinfecdis.8b00211","article-title":"Identification and mechanistic understanding of dihydroorotate dehydrogenase point mutations in Plasmodium falciparum that confer in vitro resistance to the clinical candidate DSM265","volume":"5","author":"White","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6244","DOI":"10.2174\/0929867326666190618153950","article-title":"Secondary Metabolites from Deep-Sea Derived Microorganisms","volume":"27","author":"Sun","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide:\u2009 A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/nsb0902-646","article-title":"Molecular dynamics simulations of biomolecules","volume":"9","author":"Karplus","year":"2002","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1039\/D3NP00061C","article-title":"Marine natural products","volume":"41","author":"Carroll","year":"2024","journal-title":"Nat. Prod. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1039\/C7NP00052A","article-title":"Marine natural products","volume":"35","author":"Blunt","year":"2018","journal-title":"Nat. Prod. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1039\/C9NP00069K","article-title":"Marine natural products","volume":"37","author":"Carroll","year":"2020","journal-title":"Nat. Prod. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Mayer, A.M.S., Guerrero, A.J., Rodr\u00edguez, A.D., Taglialatela-Scafati, O., Nakamura, F., and Fusetani, N. (2019). Marine pharmacology in 2014\u20132016: Marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action. Mar. Drugs, 17.","DOI":"10.3390\/md18010005"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural products as sources of new drugs","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/5\/392\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T05:29:54Z","timestamp":1772342994000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/5\/392"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,27]]},"references-count":41,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["biology15050392"],"URL":"https:\/\/doi.org\/10.3390\/biology15050392","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,27]]}}}