Identification and validation of a potent dual inhibitor of the P. falciparum M1 and M17 aminopeptidases using virtual screening

Chiara Ruggeri, Nyssa Drinkwater, Komagal Kannan Sivaraman, Rebecca S Bamert, Sheena McGowan, Alessandro Paiardini

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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.
Original languageEnglish
Article numbere0138957
Number of pages16
JournalPLoS ONE
Issue number9
Publication statusPublished - 2015

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