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One promising target is the single\u2010stranded DNA\u2010binding protein (PfSSB) of <jats:italic>Plasmodium falciparum<\/jats:italic>, crucial for DNA replication process in apicoplast, an essential organelle. Using an integrative approach, PPG and 9\u2010HPF are identified, which inhibit the DNA binding property of PfSSB and exhibit antimalarial activity. Computational analyses reveal that both compounds possess strong binding affinity and favorable drug\u2010like properties. Biolayer interferometry assay and the gel retardation assays demonstrate that they have a stronger binding affinity and disrupt PfSSB's ssDNA binding ability. PPG and 9\u2010HPF show antimalarial activity against drug\u2010sensitive <jats:italic>P. falciparum<\/jats:italic> (3D7) with IC<jats:sub>50<\/jats:sub> values of 54.95 and 9.13\u2009\u03bcM, respectively, and they can also effectively inhibit artemisinin\u2010resistant <jats:italic>P. falciparum<\/jats:italic> (C580Y) with a resistance index of 0.79 and 1.26, respectively. MTT cytotoxicity assays confirm that both compounds are nontoxic, and structural similarity analysis indicates that they are distinct from existing antimalarials, reducing cross\u2010resistance risk. Additionally, virtual screening of 59,807 compounds with similar structures to PPG and 9\u2010HPF identifies candidates with higher affinities for PfSSB. This study identifies PPG and 9\u2010HPF as structurally distinct antimalarials with the potential to combat drug\u2010resistant <jats:italic>P. falciparum.<\/jats:italic><\/jats:p>","DOI":"10.1002\/cmdc.202500282","type":"journal-article","created":{"date-parts":[[2025,9,14]],"date-time":"2025-09-14T13:24:44Z","timestamp":1757856284000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting <i>Plasmodium falciparum<\/i> Single\u2010Stranded DNA\u2010Binding Protein: Discovery of New Scaffold Compounds Effective against Drug\u2010Sensitive and Artemisinin\u2010Resistant Strains"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3732-5063","authenticated-orcid":false,"given":"Biswajit","family":"Naik","sequence":"first","affiliation":[{"name":"Department of Biochemistry School of Life Sciences Central University of Rajasthan  Bandarsindri Ajmer Rajasthan 305817 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preshita","family":"Bhalerao","sequence":"additional","affiliation":[{"name":"Department of Biotechnology School of Life Sciences Central University of Rajasthan  Bandarsindri Ajmer Rajasthan 305817 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashank","family":"Shekhar","sequence":"additional","affiliation":[{"name":"Special Centre for Molecular Medicine Jawaharlal Nehru University  New Delhi 110067 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephy A.","family":"Varghese","sequence":"additional","affiliation":[{"name":"Special Centre for Molecular Medicine Jawaharlal Nehru University  New Delhi 110067 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sweta","family":"Makwana","sequence":"additional","affiliation":[{"name":"Department of Biochemistry School of Life Sciences Central University of Rajasthan  Bandarsindri Ajmer Rajasthan 305817 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandi C.","family":"Mandal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry School of Life Sciences Central University of Rajasthan  Bandarsindri Ajmer Rajasthan 305817 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarun Kumar","family":"Bhatt","sequence":"additional","affiliation":[{"name":"Department of Biotechnology School of Life Sciences Central University of Rajasthan  Bandarsindri Ajmer Rajasthan 305817 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman Kumar","family":"Dhar","sequence":"additional","affiliation":[{"name":"Special Centre for Molecular Medicine Jawaharlal Nehru University  New Delhi 110067 India"},{"name":"TERI School of Advanced Studies Institutional Area  Vasant Kunj New Delhi 110070 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-5473","authenticated-orcid":false,"given":"Dhaneswar","family":"Prusty","sequence":"additional","affiliation":[{"name":"Department of Biochemistry School of Life Sciences Central University of Rajasthan  Bandarsindri Ajmer Rajasthan 305817 India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.30875\/9789287076717"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00772-9"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a025619"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-016-1675-x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20170563"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003335107"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2016.08.005"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr200258w"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq565"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm960352"},{"key":"e_1_2_10_12_1","volume-title":"Antimalarial Drugs: An Overview","author":"Travassos M.","year":"2017"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39914-3"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/10409230802341296"},{"key":"e_1_2_10_15_1","first-page":"1","author":"Naik B.","year":"2024","journal-title":"J. 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