PDBsum entry 4zqt

Hydrolase/hydrolase inhibitor

PDB id: 4zqt

Contents

Protein chain

889 a.a.

Ligands

4QP

GOL ×2

Metals

_MG

_ZN

Waters ×903

PDB id:

4zqt

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of pfa-m1 with virtual ligand inhibitor

Structure:

M1 family aminopeptidase. Chain: a. Fragment: unp residues 196-1084. Synonym: pfa-m1. Engineered: yes

Source:

Plasmodium falciparum 3d7. Organism_taxid: 36329. Strain: isolate 3d7. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.98Å R-factor: 0.161 R-free: 0.210

Authors:

C.Ruggeri,N.Drinkwater,S.Mcgowan

Key ref:

C.Ruggeri et al. (2015). Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening. Plos One, 10, e0138957. PubMed id: 26406322 DOI: 10.1371/journal.pone.0138957

Date:

11-May-15 Release date: 07-Oct-15

Protein chain

O96935  (AMP1_PLAFQ) -  Aminopeptidase N from Plasmodium falciparum (isolate 3D7)

Seq: 1085 a.a.

Struc: 889 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.11.- - ?????

DOI no: 10.1371/journal.pone.0138957

Plos One 10:e0138957 (2015)

PubMed id: 26406322

Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening.

C.Ruggeri, N.Drinkwater, K.K.Sivaraman, R.S.Bamert, S.McGowan, A.Paiardini.

ABSTRACT

The Plasmodium falciparum PfA-M1 and PfA-M17 metalloaminopeptidases are validated drug targets for the discovery of antimalarial agents. In order to identify dual inhibitors of both proteins, we developed a hierarchical virtual screening approach, followed by in vitro evaluation of the highest scoring hits. Starting from the ZINC database of purchasable compounds, sequential 3D-pharmacophore and molecular docking steps were applied to filter the virtual 'hits'. At the end of virtual screening, 12 compounds were chosen and tested against the in vitro aminopeptidase activity of both PfA-M1 and PfA-M17. Two molecules showed significant inhibitory activity (low micromolar/nanomolar range) against both proteins. Finally, the crystal structure of the most potent compound in complex with both PfA-M1 and PfA-M17 was solved, revealing the binding mode and validating our computational approach.