4Z22

structure of plasmepsin II from Plasmodium Falciparum complexed with inhibitor DR718A

Summary for 4Z22

• Entry DOI: 10.2210/pdb4z22/pdb
• Descriptor: Plasmepsin-2, 2-amino-7-phenyl-3-{[(2R,5S)-5-phenyltetrahydrofuran-2-yl]methyl}quinazolin-4(3H)-one (3 entities in total)
• Functional Keywords: plasmepsin ii, malaria, inhibitor, hydrolase
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 2
• Total formula weight: 74614.17

Authors

Recacha, R.,Leitans, J.,Tars, K.,Jaudzems, K. (deposition date: 2015-03-28, release date: 2016-01-13, Last modification date: 2024-10-09)

Primary citation

Rasina, D.,Otikovs, M.,Leitans, J.,Recacha, R.,Borysov, O.V.,Kanepe-Lapsa, I.,Domraceva, I.,Pantelejevs, T.,Tars, K.,Blackman, M.J.,Jaudzems, K.,Jirgensons, A.
Fragment-Based Discovery of 2-Aminoquinazolin-4(3H)-ones As Novel Class Nonpeptidomimetic Inhibitors of the Plasmepsins I, II, and IV.
J.Med.Chem., 59:374-387, 2016

PubMed Abstract: 2-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 ∼ 1 μM. Together, these results suggest 2-aminoquinazolin-4(3H)-ones as perspective leads for future development of an antimalarial agent.

PubMed: 26670264
DOI: 10.1021/acs.jmedchem.5b01558

Experimental method

X-RAY DIFFRACTION (2.62 Å)