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The four vacuolar plasmepsins (PM<\/jats:styled-content>s) in Plasmodium falciparum<\/jats:italic> involved in hemoglobin (Hb) catabolism represent promising targets to combat drug resistance. High antimalarial activities can be achieved by developing a single drug that would simultaneously target all the vacuolar PM<\/jats:styled-content>s. We have demonstrated for the first time the use of soluble recombinant plasmepsin II (PMII<\/jats:styled-content>) for structure\u2010guided drug discovery with KNI<\/jats:styled-content> inhibitors. Compounds used in this study (KNI<\/jats:styled-content>\u201010742, 10743, 10395, 10333, and 10343) exhibit nanomolar inhibition against PMII<\/jats:styled-content> and are also effective in blocking the activities of PMI<\/jats:styled-content> and PMIV<\/jats:styled-content> with the low nanomolar K<\/jats:italic>i<\/jats:sub> values. The high\u2010resolution crystal structures of PMII<\/jats:styled-content>\u2013KNI<\/jats:styled-content> inhibitor complexes reveal interesting features modulating their differential potency. Important individual characteristics of the inhibitors and their importance for potency have been established. The alkylamino analog, KNI<\/jats:styled-content>\u201010743, shows intrinsic flexibility at the P2 position that potentiates its interactions with Asp132, Leu133, and Ser134. The phenylacetyl tripeptides, KNI<\/jats:styled-content>\u201010333 and KNI<\/jats:styled-content>\u201010343, accommodate different \u03c1\u2010substituents at the P3 phenylacetyl ring that determine the orientation of the ring, thus creating novel hydrogen\u2010bonding contacts. KNI<\/jats:styled-content>\u201010743 and KNI<\/jats:styled-content>\u201010333 possess significant antimalarial activity, block Hb degradation inside the food vacuole, and show no cytotoxicity on human cells; thus, they can be considered as promising candidates for further optimization. Based on our structural data, novel KNI<\/jats:styled-content> derivatives with improved antimalarial activity could be designed for potential clinical use.<\/jats:p><\/jats:sec>Database<\/jats:title>Structural data are available in the PDB<\/jats:styled-content> under the accession numbers 5YIE<\/jats:ext-link>, 5YIB<\/jats:ext-link>, 5YID<\/jats:ext-link>, 5YIC<\/jats:ext-link>, and 5YIA<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.14598","type":"journal-article","created":{"date-parts":[[2018,6,26]],"date-time":"2018-06-26T10:19:02Z","timestamp":1530008342000},"page":"3077-3096","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Deciphering the mechanism of potent peptidomimetic inhibitors targeting plasmepsins \u2013 biochemical and structural insights"],"prefix":"10.1111","volume":"285","author":[{"given":"Vandana","family":"Mishra","sequence":"first","affiliation":[{"name":"Department of 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