4z22
From Proteopedia
structure of plasmepsin II from Plasmodium Falciparum complexed with inhibitor DR718A
Structural highlights
FunctionPLM2_PLAFX During the asexual blood stage, participates in initial cleavage of native host hemoglobin (Hb) resulting in Hb denaturation (PubMed:8844673, PubMed:11782538, PubMed:15574427). May cleave preferentially denatured hemoglobin that has been cleaved by PMI (PubMed:8844673). Digestion of host Hb is an essential step which provides the parasite with amino acids for protein synthesis, and regulates osmolarity (Probable).[1] [2] [3] Publication Abstract from PubMed2-Aminoquinazolin-4(3H)-ones were identified as a novel class of malaria digestive vacuole plasmepsin inhibitors by using NMR-based fragment screening against Plm II. Initial fragment hit optimization led to a submicromolar inhibitor, which was cocrystallized with Plm II to produce an X-ray structure of the complex. The structure showed that 2-aminoquinazolin-4(3H)-ones bind to the open flap conformation of the enzyme and provided clues to target the flap pocket. Further improvement in potency was achieved via introduction of hydrophobic substituents occupying the flap pocket. Most of the 2-aminoquinazolin-4(3H)-one based inhibitors show a similar activity against digestive Plms I, II, and IV and >10-fold selectivity versus CatD, although varying the flap pocket substituent led to one Plm IV selective inhibitor. In cell-based assays, the compounds show growth inhibition of Plasmodium falciparum 3D7 with IC50 approximately 1 muM. Together, these results suggest 2-aminoquinazolin-4(3H)-ones as perspective leads for future development of an antimalarial agent. Fragment-Based Discovery of 2-Aminoquinazolin-4(3H)-ones As Novel Class Nonpeptidomimetic Inhibitors of the Plasmepsins I, II, and IV.,Rasina D, Otikovs M, Leitans J, Recacha R, Borysov OV, Kanepe-Lapsa I, Domraceva I, Pantelejevs T, Tars K, Blackman MJ, Jaudzems K, Jirgensons A J Med Chem. 2015 Dec 23. PMID:26670264[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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