{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T22:07:21Z","timestamp":1771798041127,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T00:00:00Z","timestamp":1650499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Major National Science and Technology Program of China for Innovative Drug","award":["2017ZX09101002-001-001"],"award-info":[{"award-number":["2017ZX09101002-001-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Malaria chemotherapy is greatly threatened by the recent emergence and spread of resistance in the Plasmodium falciparum parasite against artemisinins and their partner drugs. Therefore, it is an urgent priority to develop new antimalarials. Plasmepsin V (PMV) is regarded as a superior drug target for its essential role in protein export. In this study, we performed virtual screening based on homology modeling of PMV structure, molecular docking and pharmacophore model analysis against a library with 1,535,478 compounds, which yielded 233 hits. Their antimalarial activities were assessed amongst four non-peptidomimetic compounds that demonstrated the promising inhibition of parasite growth, with mean IC50 values of 6.67 \u03bcM, 5.10 \u03bcM, 12.55 \u03bcM and 8.31 \u03bcM. No significant affection to the viability of L929 cells was detected in these candidates. These four compounds displayed strong binding activities with the PfPMV model through H-bond, hydrophobic, halogen bond or \u03c0-\u03c0 interactions in molecular docking, with binding scores under \u22129.0 kcal\/mol. The experimental validation of molecule-protein interaction identified the binding of four compounds with multiple plasmepsins; however, only compound 47 showed interaction with plasmepsin V, which exhibited the potential to be developed as an active PfPMV inhibitor.<\/jats:p>","DOI":"10.3390\/molecules27092670","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T21:39:45Z","timestamp":1650749985000},"page":"2670","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["In Silico and In Vitro Antimalarial Screening and Validation Targeting Plasmodium falciparum Plasmepsin V"],"prefix":"10.3390","volume":"27","author":[{"given":"Xin","family":"Ji","sequence":"first","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China"},{"name":"NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhensheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Chen","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingzhong","family":"Li","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Echinococcosis Prevention and Control, 21# Linkuo North Road, Chengguan District, Lhasa 850000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4229-8426","authenticated-orcid":false,"given":"Zenglei","family":"Wang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021, December 10). World Malaria Report, Available online: https:\/\/www.who.int\/teams\/global-malaria-programme\/reports\/world-malaria-report-2020\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1080\/14787210.2016.1220304","article-title":"Management of relapsing Plasmodium vivax malaria","volume":"14","author":"Chu","year":"2016","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.pt.2016.05.010","article-title":"Artemisinin action and resistance in Plasmodium falciparum","volume":"32","author":"Tilley","year":"2016","journal-title":"Trends Parasitol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1056\/NEJMc0805011","article-title":"Evidence of artemisinin-resistant malaria in western Cambodia","volume":"359","author":"Noedl","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1126\/science.1098876","article-title":"Intercontinental spread of pyrimethamine-resistant malaria","volume":"305","author":"Roper","year":"2004","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7049","DOI":"10.1128\/AAC.02746-14","article-title":"Delayed parasite clearance after treatment with dihydroartemisinin-piperaquine in Plasmodium falciparum malaria patients in central Vietnam","volume":"58","author":"Thriemer","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S1473-3099(17)30048-8","article-title":"The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: A molecular epidemiology observational study","volume":"17","author":"Imwong","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_8","first-page":"155","article-title":"Drug-resistant malaria advances in Mekong","volume":"358","author":"Roberts","year":"2017","journal-title":"Am. Assoc. Adv. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4445","DOI":"10.1021\/acs.jmedchem.9b01622","article-title":"Plasmepsin Inhibitors in Antimalarial Drug Discovery: Medicinal Chemistry and Target Validation (2000 to Present)","volume":"63","author":"Cheuka","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12936-016-1097-9","article-title":"Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites","volume":"15","author":"Ponsuwanna","year":"2016","journal-title":"Malaria J."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sleebs, B.E., Lopaticki, S., Marapana, D.S., O\u2019Neill, M.T., Rajasekaran, P., Gazdik, M., Gunther, S., Whitehead, L.W., Lowes, K.N., and Barfod, L. (2014). Inhibition of Plasmepsin V Activity Demonstrates Its Essential Role in Protein Export, PfEMP1 Display, and Survival of Malaria Parasites. PLoS Biol., 12.","DOI":"10.1371\/journal.pbio.1001897"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1126\/science.1102452","article-title":"Targeting malaria virulence and remodeling proteins to the host erythrocyte","volume":"306","author":"Marti","year":"2004","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1126\/science.1102737","article-title":"A host-targeting signal in virulence proteins reveals a secretome in malarial infection","volume":"306","author":"Hiller","year":"2004","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.molbiopara.2008.04.011","article-title":"N-terminal processing of proteins exported by malaria parasites","volume":"160","author":"Chang","year":"2008","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/mmi.13024","article-title":"The P lasmodium falciparum exportome contains non-canonical PEXEL\/HT proteins","volume":"97","author":"Schulze","year":"2015","journal-title":"Mol. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/nature08726","article-title":"Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte","volume":"463","author":"Russo","year":"2010","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/nsmb.3061","article-title":"Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes","volume":"22","author":"Hodder","year":"2015","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.ejmech.2018.05.022","article-title":"Enhanced antimalarial activity of plasmepsin V inhibitors by modification of the P-2 position of PEXEL peptidomimetics","volume":"154","author":"Nguyen","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gambini, L., Rizzi, L., Pedretti, A., Taglialatela-Scafati, O., Carucci, M., Pancotti, A., Galli, C., Read, M., Giurisato, E., and Romeo, S. (2015). Picomolar Inhibition of Plasmepsin V, an Essential Malaria Protease, Achieved Exploiting the Prime Region. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142509"},{"key":"ref_20","unstructured":"International Organization for Standardization (2009). Biological Evaluation of Medical Devices\u2014Part 5: In Vitro Cytotoxicity Testing, International Organization for Standardization."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nrd4163","article-title":"The role of ligand efficiency metrics in drug discovery","volume":"13","author":"Hopkins","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1365-2958.2005.04556.x","article-title":"Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance","volume":"56","author":"Bray","year":"2005","journal-title":"Mol. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1002\/med.20082","article-title":"Plasmepsins as potential targets for new antimalarial therapy","volume":"26","author":"Ersmark","year":"2006","journal-title":"Med. Res. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.biochi.2018.07.002","article-title":"In vitro and in silico studies of naphthoquinones and peptidomimetics toward Plasmodium falciparum plasmepsin V","volume":"152","author":"Sittikul","year":"2018","journal-title":"Biochimie"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sharma, P.P., Kumar, S., Kaushik, K., Singh, A., Singh, I.K., Grishina, M., Pandey, K.C., Singh, P., Potemkin, V. (2021). In silico validation of novel inhibitors of malarial aspartyl protease, plasmepsin V and antimalarial efficacy prediction. J. Biomol. Struct. Dyn., 1\u201313.","DOI":"10.1080\/07391102.2021.1911855"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"21984","DOI":"10.1073\/pnas.0910040106","article-title":"Target identification using drug affinity responsive target stability (DARTS)","volume":"106","author":"Lomenick","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D539","DOI":"10.1093\/nar\/gkn814","article-title":"PlasmoDB: A functional genomic database for malaria parasites","volume":"37","author":"Aurrecoechea","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3320","DOI":"10.1093\/nar\/gkg556","article-title":"ESPript\/ENDscript: Extracting and rendering sequence and 3D information from atomic structures of proteins","volume":"31","author":"Gouet","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_29","unstructured":"Biovia, D.S. (2016). Discovery Studio Modeling Environment, Dassault Syst\u00e8mes."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/BF00228148","article-title":"AQUA and PROCHECK-NMR: Programs for checking the quality of protein structures solved by NMR","volume":"8","author":"Laskowski","year":"1996","journal-title":"J. Biomol. NMR"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","article-title":"OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space","volume":"17","author":"Lu","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_32","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":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1126\/science.781840","article-title":"Human malaria parasites in continuous culture","volume":"193","author":"Trager","year":"1976","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"33891","DOI":"10.1038\/srep33891","article-title":"Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"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":"ref_36","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s10822-010-9352-6","article-title":"Ligand docking and binding site analysis with PyMOL and Autodock\/Vina","volume":"24","author":"Seeliger","year":"2010","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Miao, J., Wang, C.Q., Lucky, A.B., Liang, X.Y., Min, H., Adapa, S.R., Jiang, R., Kim, K., and Cui, L.W. (2021). A unique GCN5 histone acetyltransferase complex controls erythrocyte invasion and virulence in the malaria parasite Plasmodium falciparum. PLoS Pathog., 17.","DOI":"10.1101\/2021.02.03.429532"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/978-1-4939-2269-7_22","article-title":"Drug affinity responsive target stability (DARTS) for small-molecule target identification","volume":"1263","author":"Pai","year":"2015","journal-title":"Methods Mol. Biol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/9\/2670\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:58:10Z","timestamp":1760137090000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/9\/2670"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,21]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["molecules27092670"],"URL":"https:\/\/doi.org\/10.3390\/molecules27092670","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,21]]}}}