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We previously characterized the Atg8\u2013Atg3 protein\u2013protein interaction (PPI), which is essential for autophagy and parasite survival. Herein we illustrate the use of virtual library screening to selectively block the PPI in the parasite without inhibiting the homologous interaction in humans by targeting the A\u2010loop of <jats:italic>Pf<\/jats:italic>Atg8. This A\u2010loop is important for Atg3 binding in <jats:italic>Plasmodium<\/jats:italic>, but is absent from the human Atg8 homologues. In this proof\u2010of\u2010concept study, we demonstrate a shift in lipidation state of <jats:italic>Pf<\/jats:italic>Atg8 and inhibition of <jats:italic>P.\u2005falciparum<\/jats:italic> growth in both blood\u2010 and liver\u2010stage cultures upon drug treatment. Our results illustrate how in\u2005silico screening and structure\u2010aided drug design against a PPI can be used to identify new hits for drug development. Additionally, as we targeted a region of Atg8 that is conserved within apicomplexans, we predict that our small molecule will have cross\u2010reactivity against other disease\u2010causing apicomplexans, such as <jats:italic>Toxoplasma<\/jats:italic>, <jats:italic>Cryptosporidium<\/jats:italic>, <jats:italic>Theileria<\/jats:italic>, <jats:italic>Neospora<\/jats:italic>, <jats:italic>Eimeria<\/jats:italic>, and <jats:italic>Babesia<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/cmdc.201500515","type":"journal-article","created":{"date-parts":[[2016,1,10]],"date-time":"2016-01-10T09:18:02Z","timestamp":1452417482000},"page":"900-910","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Virtual Screening and Experimental Validation Identify Novel Inhibitors of the <i>Plasmodium falciparum<\/i> Atg8\u2013Atg3 Protein\u2013Protein Interaction"],"prefix":"10.1002","volume":"11","author":[{"given":"Adelaide U. 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