4ZQT

Crystal structure of PfA-M1 with virtual ligand inhibitor

Summary for 4ZQT

• Entry DOI: 10.2210/pdb4zqt/pdb
• Descriptor: M1 family aminopeptidase, (2R)-2-{[(R)-[(R)-amino(phenyl)methyl](hydroxy)phosphoryl]methyl}-4-methylpentanoic acid, ZINC ION, ... (6 entities in total)
• Functional Keywords: aminopeptidase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Plasmodium falciparum 3D7
• Total number of polymer chains: 1
• Total formula weight: 104204.81

Authors

Ruggeri, C.,Drinkwater, N.,McGowan, S. (deposition date: 2015-05-11, release date: 2015-10-07, Last modification date: 2023-09-27)

Primary citation

Ruggeri, C.,Drinkwater, N.,Sivaraman, K.K.,Bamert, R.S.,McGowan, S.,Paiardini, A.
Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening.
Plos One, 10:e0138957-e0138957, 2015

PubMed 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.

PubMed: 26406322
DOI: 10.1371/journal.pone.0138957

Experimental method

X-RAY DIFFRACTION (1.981 Å)