{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T12:42:25Z","timestamp":1763037745090,"version":"3.41.2"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T00:00:00Z","timestamp":1653436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Recent reports of resistance to artemisinin-based combination drugs necessitate the need to discover novel antimalarial compounds. The present study was aimed at identifying novel antimalarial compounds from natural product libraries using computational methods. <jats:italic>Plasmodium falciparum<\/jats:italic> is highly dependent on the pyrimidine biosynthetic pathway, a <jats:italic>de novo<\/jats:italic> pathway responsible for the production of pyrimidines, and the parasite lacks the pyrimidine salvage enzymes. The <jats:italic>P. falciparum<\/jats:italic> thymidylate monophosphate kinase (<jats:italic>Pf<\/jats:italic>TMPK) is an important protein necessary for rapid DNA replication; however, due to its broad substrate specificity, the protein is distinguished from its homologs, making it a suitable drug target. Compounds from AfroDB, a database of natural products originating from Africa, were screened virtually against <jats:italic>Pf<\/jats:italic>TMPK after filtering the compounds for absorption, distribution, metabolism, excretion, and toxicity (ADMET)-acceptable compounds with FAF-Drugs4. Thirteen hits with lower binding energies than thymidine monophosphate were selected after docking. Among the thirteen compounds, ZINC13374323 and ZINC13365918 with binding energies of \u22129.4 and \u22128.9 kcal\/mol, respectively, were selected as plausible lead compounds because they exhibited structural properties that ensure proper binding at the active site and inhibitory effect against <jats:italic>Pf<\/jats:italic>TMPK. ZINC13374323 (also called aurantiamide acetate) is known to exhibit anti-inflammatory and antiviral activities, and ZINC13365918 exhibits antileishmanial activity. Furthermore, aurantiamide acetate, which is commercially available, is a constituent of <jats:italic>Artemisia annua<\/jats:italic>, the herb from which artemisinin was derived. The compound also shares interactions with several residues with a potent thymidine analog inhibitor of <jats:italic>Pf<\/jats:italic>TMPK. The anti-plasmodial activity of aurantiamide acetate was evaluated <jats:italic>in vitro<\/jats:italic>, and the mean half-maximal inhibitory concentration (IC<jats:sub>50<\/jats:sub>) was 69.33 \u03bcM when synchronized <jats:italic>P. falciparum<\/jats:italic> 3D7 culture was used as compared to IC<jats:sub>50<\/jats:sub> &amp;gt; 100 \u03bcM with asynchronized culture. The significance of our findings within the context of malaria treatment strategies and challenges is discussed.<\/jats:p>","DOI":"10.3389\/fcimb.2022.868529","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T05:14:01Z","timestamp":1653455641000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting the Plasmodium falciparum\u2019s Thymidylate Monophosphate Kinase for the Identification of Novel Antimalarial Natural Compounds"],"prefix":"10.3389","volume":"12","author":[{"given":"Kweku S.","family":"Enninful","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel K.","family":"Kwofie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Tetteh-Tsifoanya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda N. L.","family":"Lamptey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgina","family":"Djameh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Nyarko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Ghansah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1186\/s12936-021-03955-0","article-title":"Network-Driven Analysis of Human\u2013Plasmodium falciparum Interactome: Processes for Malaria Drug Discovery and Extracting In Silico Targets","volume":"20","author":"Agamah","year":"2021","journal-title":"Malar. J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3875","DOI":"10.2147\/DDDT.S265602","article-title":"Recent Progress in the Development of New Antimalarial Drugs With Novel Targets","volume":"14","author":"Belete","year":"2020","journal-title":"Drug Des. Devel. Ther."},{"key":"B3","doi-asserted-by":"publisher","first-page":"169","DOI":"10.2174\/157340906777441663","article-title":"Structural Alerts of Mutagens and Carcinogens","volume":"2","author":"Benigni","year":"2006","journal-title":"Curr. Comput. Aided-Drug Des."},{"key":"B4","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/nature15535","article-title":"The Effect of Malaria Control on Plasmodium falciparum in Africa Between 2000 and 2015","volume":"526","author":"Bhatt","year":"2015","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.2174\/156802611796575948","article-title":"Purine and Pyrimidine Pathways as Targets in Plasmodium falciparum","volume":"11","author":"Cassera","year":"2011","journal-title":"Curr. Top. Med. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2868","DOI":"10.1021\/acs.biochem.8b00162","article-title":"Interaction of \u03b1-Thymidine Inhibitors With Thymidylate Kinase From Plasmodium falciparum","volume":"57","author":"Chen","year":"2018","journal-title":"Biochemistry"},{"key":"B7","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1021\/np050422s","article-title":"A Pyrimidine-\u03b2-Carboline and Other Alkaloids From Annona F Oetida With Antileishmanial Activity","volume":"69","author":"Costa","year":"2006","journal-title":"J. Nat. Prod."},{"key":"B8","doi-asserted-by":"publisher","first-page":"10948","DOI":"10.1021\/jm301328h","article-title":"Synthesis and Evaluation of \u03b1-Thymidine Analogues as Novel Antimalarials","volume":"55","author":"Cui","year":"2012","journal-title":"J. Med. Chem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/978-1-4939-2269-7_19","article-title":"Small-Molecule Library Screening by Docking With Pyrx","volume":"1263","author":"Dallakyan","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the Areas Under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.freeradbiomed.2021.08.016","article-title":"Resistance to Artemisinin in Falciparum Malaria Parasites: A Redox-Mediated Phenomenon","volume":"179","author":"Egwu","year":"2022","journal-title":"Free Radic. Biol. Med."},{"unstructured":"Status Report on Artemisinin and ACT Resistance2015","key":"B12"},{"key":"B13","doi-asserted-by":"publisher","first-page":"213","DOI":"10.32614\/RJ-2016-042","article-title":"Easyroc: An Interactive Web-Tool for Roc Curve Analysis Using R Language Environment","volume":"8","author":"Goksuluk","year":"2016","journal-title":"R J."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-10-S1-S2","article-title":"How can Natural Products Serve as a Viable Source of Lead Compounds for the Development of New\/Novel Anti-Malarials","volume":"10","author":"Guantai","year":"2011","journal-title":"Malar. J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.jmgm.2010.05.005","article-title":"Ligalign: Flexible Ligand-Based Active Site Alignment and Analysis","volume":"29","author":"Heifets","year":"2010","journal-title":"J. Mol. Graph. Model."},{"key":"B16","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1007\/s11418-008-0246-z","article-title":"Plant-Derived Natural Product Research Aimed at New Drug Discovery","volume":"62","author":"Itokawa","year":"2008","journal-title":"J. Nat. Med."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182008005301","article-title":"Mutational, Inhibitory and Microcalorimetric Analyses of Plasmodium falciparum TMP Kinase. Implications for Drug Discovery","volume":"136","author":"Kandeel","year":"2009","journal-title":"Parasitology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.apjtm.2016.04.012","article-title":"Insights Into the Pyrimidine Biosynthetic Pathway of Human Malaria Parasite Plasmodium falciparum as Chemotherapeutic Target","volume":"9","author":"Krungkrai","year":"2016","journal-title":"Asian Pac. J. Trop. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.biopha.2018.05.009","article-title":"Drug Targets for Resistant Malaria: Historic to Future Perspectives","volume":"104","author":"Kumar","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26020406","article-title":"Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin","volume":"26","author":"Kwofie","year":"2021","journal-title":"Molecules"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3658","DOI":"10.1093\/bioinformatics\/btx491","article-title":"Faf-Drugs4: Free ADME-Tox Filtering Computations for Chemical Biology and Early Stages Drug Discovery","volume":"33","author":"Lagorce","year":"2017","journal-title":"Bioinformatics"},{"key":"B22","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.ijpddr.2012.07.002","article-title":"In Silico Prediction of Antimalarial Drug Target Candidates","volume":"2","author":"Ludin","year":"2012","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1097\/JTO.0b013e3181ec173d","article-title":"Receiver Operating Characteristic Curve in Diagnostic Test Assessment","volume":"5","author":"Mandrekar","year":"2010","journal-title":"J. Thorac. Oncol."},{"volume-title":"Traditional Chinese Medicines: Molecular Structures, Natural Sources and Applications","year":"2018","author":"Milne","key":"B24"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e1007025","DOI":"10.1371\/journal.pcbi.1007025","article-title":"Deep Learning-driven Research for Drug Discovery: Tackling Malaria","volume":"16","author":"Neves","year":"2020","journal-title":"PLoS Comput. Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e78085","DOI":"10.1371\/journal.pone.0078085","article-title":"Afrodb: A Select Highly Potent and Diverse Natural Product Library From African Medicinal Plants","volume":"8","author":"Ntie-Kang","year":"2013","journal-title":"PLoS One"},{"key":"B27","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.biosystems.2013.07.005","article-title":"First Report on Exploring Structural Requirements of Alpha and Beta Thymidine Analogs for PfTMPK Inhibitory Activity Using Iin Silico Studies","volume":"113","author":"Ojha","year":"2013","journal-title":"BioSystems"},{"key":"B28","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1056\/NEJMp1403340","article-title":"The Origins of Antimalarial-Drug Resistance","volume":"371","author":"Packard","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"B29","doi-asserted-by":"crossref","DOI":"10.1016\/B978-0-08-101210-9.00013-5","article-title":"Kinases and Kinase Inhibitors","volume-title":"Antimalarial Agents","author":"Patrick","year":"2020"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-12-450","article-title":"A SYBR Green 1-Based In Vitro Test of Susceptibility of Ghanaian Plasmodium falciparum Clinical Isolates to a Panel of Anti-Malarial Drugs","volume":"12","author":"Quashie","year":"2013","journal-title":"Malar. J."},{"key":"B31","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/0166-6851(82)90035-4","article-title":"Enzymes of Purine and Pyrimidine Metabolism From the Human Malaria Parasite, Plasmodium Falciparum","volume":"5","author":"Reyes","year":"1982","journal-title":"Mol. Biochem. Parasitol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1021\/ci500588j","article-title":"Datawarrior: An Open-Source Program for Chemistry Aware Data Visualization And Analysis","volume":"55","author":"Sander","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"B33","first-page":"1314","article-title":"Antimalarial Agents From Plant Sources","volume":"85","author":"Saxena","year":"2003","journal-title":"Curr. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1107\/S0907444904011679","article-title":"Prodrg: A Tool for High-Throughput Crystallography of Protein-Ligand Complexes","volume":"60","author":"Sch\u00fcttelkopf","year":"2004","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"B35","first-page":"172","article-title":"Role of Natural Products in Drug Discovery Process","volume":"6","author":"Siddiqui","year":"2014","journal-title":"Int. J. Drug Dev. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1124\/pr.112.007336","article-title":"Computational Methods in Drug Discovery","volume":"66","author":"Sliwoski","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1128\/AAC.48.5.1803-1806.2004","article-title":"Simple and Inexpensive Fluorescence-Based Technique for High-Throughput Antimalarial Drug Screening","volume":"48","author":"Smilkstein","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003257","article-title":"Prediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery","volume":"9","author":"Spitzm\u00fcller","year":"2013","journal-title":"PLoS Comput. Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1186\/s12936-019-3026-1","article-title":"Antiplasmodial Natural Products: An Update","volume":"18","author":"Tajuddeen","year":"2019","journal-title":"Malar. J."},{"key":"B40","first-page":"24","article-title":"The Antimicrobial Activities of Extract and Compounds Isolated From Brillantaisia Lamium","volume":"36","author":"Tamokou","year":"2011","journal-title":"Iran. J. Med. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1186\/1472-6882-12-99","article-title":"Antioxidant and Antimicrobial Activities of Ethyl Acetate Extract, Fractions and Compounds From Stem Bark of Albizia Adianthifolia (Mimosoideae)","volume":"12","author":"Tamokou","year":"2012","journal-title":"BMC Complement. Altern. Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"043","DOI":"10.1684\/san.2008.0103","article-title":"Sensibilit\u00e9 In Vitro De P. falciparum \u00c0 La Quinine, L\u2019art\u00e9sunate Et La Chloroquine \u00c0 Abidjan (C\u00f4te d\u2019ivoire)","volume":"18","author":"Tour\u00e9","year":"2008","journal-title":"Cah. Sant\u00e9"},{"key":"B43","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"Software News and Update AutoDock Vina: Improving the Speed and Accuracy of Docking With a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"4699","DOI":"10.1111\/j.1742-4658.2007.06000.x","article-title":"Helicases - Feasible Antimalarial Drug Target for Plasmodium falciparum","volume":"274","author":"Tuteja","year":"2007","journal-title":"FEBS J."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"Gromacs: Fast, Flexible, and Free","volume":"26","author":"Van Der Spoel","year":"2005","journal-title":"J. Comput. Chem."},{"key":"B46","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/s00401-021-02394-0","article-title":"DTYMK is Essential for Genome Integrity and Neuronal Survival","volume":"143","author":"Vanoevelen","year":"2022","journal-title":"Acta Neuropathol."},{"key":"B47","first-page":"7","article-title":"Graphing With Gnuplot and Xmgr: Two Graphing Packages Available Under Linux","volume":"1996","author":"Vaught","year":"1996","journal-title":"Linux J."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1093\/bioinformatics\/btw783","article-title":"Rader: A Rapid DEcoy Retriever to Facilitate Decoy Based Assessment of Virtual Screening","volume":"33","author":"Wang","year":"2017","journal-title":"Bioinformatics"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.5497\/wjp.v3.i4.39","article-title":"Dried-Leaf Artemisia Annua: A Practical Malaria Therapeutic for Developing Countries","volume":"3","author":"Weathers","year":"2014","journal-title":"World J. Pharmacol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1042\/BJ20091880","article-title":"Structural Basis for the Efficient Phosphorylation of AZT-MP (3\u2032-azido-3\u2032-deoxythymidine Monophosphate) and dGMP by Plasmodium falciparum Type I Thymidylate Kinase","volume":"428","author":"Whittingham","year":"2010","journal-title":"Biochem. J."},{"unstructured":"World Heal. OrganStatus Report on Artemisinin Resistance and ACT Efficacy (August 2018)2018","key":"B51"},{"key":"B52","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.jep.2017.01.038","article-title":"Aurantiamide Acetate From Baphicacanthus cusia Root Exhibits Anti-Inflammatory and Anti-Viral Effects via Inhibition of the NF-\u03baB Signaling Pathway in Influenza A virus-Infected Cells","volume":"199","author":"Zhou","year":"2017","journal-title":"J. Ethnopharmacol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.868529\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T05:14:16Z","timestamp":1653455656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.868529\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,25]]},"references-count":52,"alternative-id":["10.3389\/fcimb.2022.868529"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.868529","relation":{},"ISSN":["2235-2988"],"issn-type":[{"type":"electronic","value":"2235-2988"}],"subject":[],"published":{"date-parts":[[2022,5,25]]},"article-number":"868529"}}