PDBsum entry 4z22

Hydrolase

PDB id: 4z22

Contents

Protein chains

329 a.a.

Ligands

4KG ×2

Waters ×72

PDB id:

4z22

Name:

Hydrolase

Title:

Structure of plasmepsin ii from plasmodium falciparum complexed with inhibitor dr718a

Structure:

Plasmepsin-2. Chain: a, b. Fragment: unp residues 125-453. Synonym: plasmepsin ii. Engineered: yes

Source:

Plasmodium falciparum. Organism_taxid: 5833. Gene: pfag_05140. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.62Å R-factor: 0.208 R-free: 0.253

Authors:

R.Recacha,J.Leitans,K.Tars,K.Jaudzems

Key ref:

D.Rasina et al. (2016). 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. PubMed id: 26670264 DOI: 10.1021/acs.jmedchem.5b01558

Date:

28-Mar-15 Release date: 13-Jan-16

Protein chains

P46925  (PLM2_PLAFX) -  Plasmepsin II from Plasmodium falciparum (isolate HB3)

Seq: 453 a.a.

Struc: 329 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.23.39 - plasmepsin Ii.
• Reaction: Hydrolysis of the bonds linking certain hydrophobic residues in hemoglobin or globin. Also cleaves small molecules substrates such as Ala-Leu-Glu-Arg-Thr-Phe-|-Phe(NO(2))-Ser-Phe-Pro-Thr.

DOI no: 10.1021/acs.jmedchem.5b01558

J Med Chem 59:374-387 (2016)

PubMed id: 26670264

Fragment-Based Discovery of 2-Aminoquinazolin-4(3H)-ones As Novel Class Nonpeptidomimetic Inhibitors of the Plasmepsins I, II, and IV.

D.Rasina, M.Otikovs, J.Leitans, R.Recacha, O.V.Borysov, I.Kanepe-Lapsa, I.Domraceva, T.Pantelejevs, K.Tars, M.J.Blackman, K.Jaudzems, A.Jirgensons.

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.