4ZQT

Crystal structure of PfA-M1 with virtual ligand inhibitor

4ZQT の概要

• エントリーDOI: 10.2210/pdb4zqt/pdb
• 分子名称: M1 family aminopeptidase, (2R)-2-{[(R)-[(R)-amino(phenyl)methyl](hydroxy)phosphoryl]methyl}-4-methylpentanoic acid, ZINC ION, ... (6 entities in total)
• 機能のキーワード: aminopeptidase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Plasmodium falciparum 3D7
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 104204.81

構造登録者

Ruggeri, C.,Drinkwater, N.,McGowan, S. (登録日: 2015-05-11, 公開日: 2015-10-07, 最終更新日: 2023-09-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.981 Å)