title: Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening.
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.
authors.affiliation: Dipartimento di Scienze biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ruggeri
authors.affiliation: Department of Microbiology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia.
authors.forename: Nyssa
authors.initials: N
authors.lastname: Drinkwater
authors.affiliation: Department of Microbiology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia.
authors.forename: Komagal Kannan
authors.initials: KK
authors.lastname: Sivaraman
authors.affiliation: Department of Microbiology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Bamert
authors.affiliation: Department of Microbiology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia.
authors.forename: Sheena
authors.initials: S
authors.lastname: McGowan
authors.affiliation: Dipartimento di Biologia e Biotecnologie "Charles Darwin", Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Paiardini
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000201:enzymology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D000626:Aminopeptidases