Design and discovery of plasmepsin II inhibitors using an automated workflow on large-scale grids.
Novel and potent inhibitors of Plasmodium falciparum plasmepsin II were identified by post-processing the results of a docking screening with BEAR, a recently reported procedure for the refinement and rescoring of docked ligands in virtual screening. FRET substrate degradation assays performed on the 30 most promising compounds resulted in 26 inhibitors with IC(50) values ranging from 4.3 nM to 1.8 microM.Herein we report the discovery of novel and potent inhibitors of Plasmodium falciparum plasmepsin II using GRID computing infrastructures. These compounds were identified by post-processing the results of a large docking screen of commercially available compounds using an automated procedure based on molecular dynamics refinement and binding free-energy estimation using MM-PBSA and MM-GBSA. Among the best-scored compounds, four highly populated and promising chemical classes were identified: N-alkoxyamidines, guanidines, amides, and ureas and thioureas. Thirty hit compounds representative of each class were selected on the basis of their favourable binding free energies and molecular interactions with key active site residues. These were experimentally validated using an inhibition assay based on FRET substrate degradation. Remarkably, 26 of the 30 tested compounds proved to be active as plasmepsin II inhibitors, with IC(50) values ranging from 4.3 nM to 1.8 microM.
Dipartimento di Scienze Farmaceutiche, Università di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy.
Gianluca
G
Degliesposti
Vinod
V
Kasam
Ana
A
Da Costa
Hee-Kyoung
HK
Kang
Nahyun
N
Kim
Do-Won
DW
Kim
Vincent
V
Breton
Doman
D
Kim
Giulio
G
Rastelli
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012984:Software
D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II