{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:51Z","timestamp":1788998451219,"version":"build-2803163510"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"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>Malaria, a parasitic disease, remains a major global health concern, with over 260 million cases reported worldwide in 2023. As resistance to current antimalarial drugs increases, the demand for ongoing research into new therapeutic targets and strategies grows. Glycogen synthase kinase (pfGSK3\u03b2) is a crucial enzyme involved in metabolic processes of the malaria parasite. In this research, an in silico study was conducted to explore this enzyme as a potential target for drug repurposing. A Python program was used to mine and extract data from the CHEMBL database, which yielded 53 potential GSK-3\u03b2 inhibitors. Subsequent in silico studies included molecular docking, molecular dynamics simulations (MD, run at 100 ns on GROMACS 2023 1), and molecular mechanics Poisson-Boltzmann surface area (MMPBSA). In silico data analysis identified three potential drug molecules: S20-CHEMBLID 1910196 (4-[5-(6- hydroxy- 1H-indol-2- yl)pyridin-3- yl]benzonitrile), S39-CHEMBL ID 2321945 (2-(7- bromo- 2- hydroxy- 1H-indol-3-yl)-3- oxoindole- 6- carboxylic acid), and S56-CHEMBL ID 2321951 (methyl 2-(2- hydroxy-1H-indol-3-yl)-3-nitroso-1H-indole-5-carboxylate),which could inhibit pfgsk 3\u03b2. Compound S56 demonstrated better in silico performance than S1 \u2013 (3,6- diamino- 4-(2- chlorophenyl)thieno[2, 3- b] pyridine- 2, 5-,5-dicarbonitrile), the co-crystallised ligand in pfgsk 3 \u03b2 used as a control. The binding affinities of S1 and S56 are- 7.1157074 (10 ligand interactions) and \u2013 5.64057302 (12 ligand interactions), respectively. The MD runs yielded average root-mean-square deviations (RMSDs) of 4.5\u2009nm for S1 and 1.0\u2009nm for S56. Furthermore, the root mean square fluctuation (RMSF) of S1 showed greater fluctuation between 0\u20131000 atoms compared to S56. MMPBSA analysis revealed comparable total energies: S56 was \u221214.45 kj\/mol and S1 was \u221213.03 kj\/mol. An in silico toxicity study using Protox III indicated the possible toxicity of the repurposed compounds. In conclusion, we propose that molecules S39, S20, and S56 could be repurposed as potential anti-malaria drugs.<\/jats:p>","DOI":"10.1371\/journal.pone.0326834","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T18:35:34Z","timestamp":1765218934000},"page":"e0326834","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["RETRACTED: In silico investigation of novel Plasmodium Falciparum glycogen synthase kinase (pfGSk3\u03b2) inhibitors for the treatment of malaria infection"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2655-5699","authenticated-orcid":true,"given":"Kassim Folorunsho","family":"Adebambo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6682-6764","authenticated-orcid":true,"given":"Sara","family":"Otify","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"issue":"6","key":"pone.0326834.ref001","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.jinf.2016.02.001","article-title":"UK malaria treatment guidelines 2016","volume":"72","author":"DG Lalloo","year":"2016","journal-title":"J Infect"},{"issue":"3","key":"pone.0326834.ref002","doi-asserted-by":"crossref","first-page":"384","DOI":"10.47665\/tb.39.3.008","article-title":"Medicinal plants with antimalarial activities mediated via glycogen synthase kinase-3 beta (GSK3\u03b2) inhibition","volume":"39","author":"WRM Hassan","year":"2022","journal-title":"Trop Biomed"},{"key":"pone.0326834.ref003","author":"Travel Health Pro","year":"2018"},{"key":"pone.0326834.ref004","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1186\/1471-2458-14-1129","article-title":"Preventing malaria in international travellers: an evaluation of published English-language guidelines","volume":"14","author":"M Kliner","year":"2014","journal-title":"BMC Public Health"},{"key":"pone.0326834.ref005","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.actatropica.2011.04.020","article-title":"Plasmodium berghei NK65 induces cerebral leukocyte recruitment in vivo: an intravital microscopic study","volume":"120","author":"N Lacerda-Queiroz","year":"2011","journal-title":"Acta Trop"},{"issue":"1","key":"pone.0326834.ref006","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1186\/s12864-016-2949-y","article-title":"Determining the mode of action of anti-mycobacterial C17 diyne natural products using expression profiling: evidence for fatty acid biosynthesis inhibition","volume":"17","author":"H Li","year":"2016","journal-title":"BMC Genomics"},{"key":"pone.0326834.ref007","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1172\/JCI21682","article-title":"Antimalarial drug resistance","volume":"113","author":"J White","year":"2004","journal-title":"J Clin Invest"},{"issue":"3","key":"pone.0326834.ref008","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/S1471-4914(01)02266-3","article-title":"Glycogen synthase kinase 3: an emerging therapeutic target","volume":"8","author":"H Eldar-Finkelman","year":"2002","journal-title":"Trends Mol Med"},{"key":"pone.0326834.ref009","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1016\/j.bbapap.2015.03.013","article-title":"Selective inhibitors of Plasmodium falciparum glycogen synthase-3 (PfGSK-3): New antimalarial agents?","volume":"1854","author":"A Masch","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"pone.0326834.ref010","unstructured":"Drugbank. Threonine. 2005. https:\/\/go.drugbank.com\/drugs\/DB00156"},{"key":"pone.0326834.ref011","unstructured":"Drugbank. Serine. Go.drugbank.com. [2005b, June 13]. https:\/\/go.drugbank.com\/drugs\/DB00133"},{"key":"pone.0326834.ref012","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/1471-2164-5-79","article-title":"Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote","volume":"5","author":"P Ward","year":"2004","journal-title":"BMC Genomics"},{"issue":"1","key":"pone.0326834.ref013","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/s42003-021-01873-0","article-title":"The catalytic subunit of Plasmodium falciparum casein kinase 2 is essential for gametocytogenesis","volume":"4","author":"E Hitz","year":"2021","journal-title":"Commun Biol"},{"issue":"4","key":"pone.0326834.ref014","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01896-19","article-title":"Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers","volume":"64","author":"P Sinxadi","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"issue":"10","key":"pone.0326834.ref015","doi-asserted-by":"crossref","DOI":"10.1093\/cid\/ciaa368","article-title":"A Phase 1, Placebo-controlled, Randomized, Single Ascending Dose Study and a Volunteer Infection Study to Characterize the Safety, Pharmacokinetics, and Antimalarial Activity of the Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048","volume":"71","author":"JS McCarthy","year":"2020","journal-title":"Clin Infect Dis"},{"issue":"5","key":"pone.0326834.ref016","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.3000264","article-title":"Cyclic AMP signalling controls key components of malaria parasite host cell invasion machinery","volume":"17","author":"A Patel","year":"2019","journal-title":"PLoS Biol"},{"issue":"9","key":"pone.0326834.ref017","doi-asserted-by":"crossref","first-page":"102360","DOI":"10.1016\/j.jbc.2022.102360","article-title":"Functional inactivation of Plasmodium falciparum glycogen synthase kinase GSK3 modulates erythrocyte invasion and blocks gametocyte maturation","volume":"298","author":"A Alder","year":"2022","journal-title":"J Biol Chem"},{"key":"pone.0326834.ref018","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1021\/jm301575n","article-title":"3,6-Diamino-4-(2-Halophenyl)-2-Benzoylthieno(2,3-B) Pyridine-5-Carbonitriles are Selective Inhibitors of Plasmodium Falciparum Glycogen Synthase Kinase-3 (Pfgsk-3)","volume":"56","author":"W Fugel","year":"2013","journal-title":"J Med Chem"},{"key":"pone.0326834.ref019","article-title":"Ongoing challenges in the management of malaria","author":"G Kokwaro","year":"2009","journal-title":"Malaria"},{"key":"pone.0326834.ref020","doi-asserted-by":"crossref","first-page":"9375","DOI":"10.1021\/acs.jmedchem.9b00359","article-title":"Overview of Recent Strategic Advances in Medicinal Chemistry","volume":"62","author":"G Wu","year":"2019","journal-title":"Journal of Medicinal Chemistry"},{"issue":"10","key":"pone.0326834.ref021","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1016\/j.drudis.2019.06.014","article-title":"Drug repurposing: a promising tool to accelerate the drug discovery process","volume":"24","author":"V Parvathaneni","year":"2019","journal-title":"Drug Discov Today"},{"key":"pone.0326834.ref022","article-title":"Artificial intelligence in virtual screening: Models versus experiments","volume":"18","author":"N Arul Murugan","year":"2022","journal-title":"Drug Discov Today"},{"key":"pone.0326834.ref023","article-title":"Structure-based drug repurposing: Traditional and advanced AI\/ML-aided methods","author":"C Choudhury","year":"2022","journal-title":"Drug Discov Today"},{"key":"pone.0326834.ref024","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4842-6399-0","volume-title":"A Python data analyst\u2019s toolkit: Learn Python and Python-based libraries with applications in data analysis and statistics","author":"G Rajagopalan","year":"2021"},{"key":"pone.0326834.ref025","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkr777","article-title":"ChEMBL: a large-scale bioactivity database for drug discovery","volume":"40","author":"A Gaulton","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"pone.0326834.ref026","unstructured":"Nowotka M, Papadatos G, Davies M, Dedman N, Hersey A. Want drugs? Use Python. In: Proceedings of the 8th Eur. Conf. on Python in Science (EuroSciPy 2015). 2015."},{"key":"pone.0326834.ref027","author":"Chemical Computing Group","year":"2024"},{"key":"pone.0326834.ref028","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/978-1-59745-177-2_19","article-title":"Molecular docking","volume":"443","author":"GM Morris","year":"2008","journal-title":"Methods Mol Biol"},{"issue":"1","key":"pone.0326834.ref029","doi-asserted-by":"crossref","first-page":"5068","DOI":"10.33011\/livecoms.1.1.5068","article-title":"From proteins to perturbed hamiltonians: A suite of tutorials for the gromacs-2018 molecular simulation package, v1.0","volume":"1","author":"JA Lemkul","year":"2018","journal-title":"Living J Comp Mol Sci"},{"issue":"7","key":"pone.0326834.ref030","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"g_mmpbsa--a GROMACS tool for high-throughput MM-PBSA calculations","volume":"54","author":"R Kumari","year":"2014","journal-title":"J Chem Inf Model"},{"issue":"1","key":"pone.0326834.ref031","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2133\/dmpk.DMPK-10-RV-062","article-title":"Mechanisms of drug toxicity and relevance to pharmaceutical development","volume":"26","author":"FP Guengerich","year":"2011","journal-title":"Drug Metab Pharmacokinet"},{"key":"pone.0326834.ref032","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: a webserver for the prediction of toxicity of chemicals","volume":"52","author":"P Banerjee","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"pone.0326834.ref033","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ejphar.2018.10.016","article-title":"In silico approaches for screening molecular targets in Candida albicans: A proteomic insight into drug discovery and development","volume":"842","author":"DR Silva","year":"2019","journal-title":"Eur J Pharmacol"},{"issue":"1","key":"pone.0326834.ref034","article-title":"Molecular Docking: From Lock and Key to Combination Lock","volume":"2","author":"A Tripathi","year":"2017","journal-title":"J Mol Med Clin Appl"},{"key":"pone.0326834.ref035","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1016\/j.csbj.2022.04.025","article-title":"Contribution of hydrophobic interactions to protein mechanical stability","volume":"20","author":"GG Ferenczy","year":"2022","journal-title":"Comput Struct Biotechnol J"},{"issue":"3","key":"pone.0326834.ref036","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1021\/acs.jcim.9b01143","article-title":"Combinatorial Effect of Ligand and Ligand-Binding Site Hydrophobicities on Binding Affinity","volume":"60","author":"DK Sriramulu","year":"2020","journal-title":"J Chem Inf Model"},{"key":"pone.0326834.ref037","doi-asserted-by":"crossref","DOI":"10.1002\/9783527633326.ch12","article-title":"Applications and success stories in virtual screening","volume-title":"Virtual screening: principles, challenges, and practical guidelines","author":"H Matter","year":"2011"},{"issue":"11","key":"pone.0326834.ref038","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":"DB Kitchen","year":"2004","journal-title":"Nat Rev Drug Discov"},{"issue":"9","key":"pone.0326834.ref039","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":"11","key":"pone.0326834.ref040","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.3390\/ijms20112783","article-title":"A Structure-Based Drug Discovery Paradigm","volume":"20","author":"M Batool","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"4","key":"pone.0326834.ref041","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/j.neuron.2024.01.004","article-title":"Advances in structure-based drug design: The potential for precision therapeutics in psychiatric disorders","volume":"112","author":"D Cao","year":"2024","journal-title":"Neuron"},{"issue":"2","key":"pone.0326834.ref042","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.sbi.2007.12.007","article-title":"Molecular simulation as an aid to experimentalists","volume":"18","author":"WF van Gunsteren","year":"2008","journal-title":"Curr Opin Struct Biol"},{"key":"pone.0326834.ref043","article-title":"Molecular dynamics simulation of site-directed spin labelling: experimental validation in muscle fibers","volume":"82","author":"LEW LaConte","year":"2002","journal-title":"Biophys J"},{"issue":"23","key":"pone.0326834.ref044","doi-asserted-by":"crossref","first-page":"5838","DOI":"10.1002\/chem.200305147","article-title":"Molecular dynamics simulations of small peptides: can one derive conformational preferences from ROESY spectra?","volume":"9","author":"C Peter","year":"2003","journal-title":"Chemistry"},{"issue":"3","key":"pone.0326834.ref045","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1021\/ct7000045","article-title":"Validation of Molecular Dynamics Simulations of Biomolecules Using NMR Spin Relaxation as Benchmarks:\u2009 Application to the AMBER99SB Force Field","volume":"3","author":"SA Showalter","year":"2007","journal-title":"J Chem Theory Comput"},{"issue":"4","key":"pone.0326834.ref046","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1021\/ja9093692","article-title":"Enhanced conformational space sampling improves the prediction of chemical shifts in proteins","volume":"132","author":"PRL Markwick","year":"2010","journal-title":"J Am Chem 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