title: Computational and biophysical approaches to protein-protein interaction inhibition of Plasmodium falciparum AMA1/RON2 complex.
abstract: Invasion of the red blood cell by Plasmodium falciparum parasites requires formation of an electron dense circumferential ring called the Moving Junction (MJ). The MJ is anchored by a high affinity complex of two parasite proteins: Apical Membrane Antigen 1 (PfAMA1) displayed on the surface of the parasite and Rhoptry Neck Protein 2 that is discharged from the parasite and imbedded in the membrane of the host cell. Structural studies of PfAMA1 revealed a conserved hydrophobic groove localized to the apical surface that coordinates RON2 and invasion inhibitory peptides. In the present work, we employed computational and biophysical methods to identify competitive P. falciparum AMA1-RON2 inhibitors with the goal of exploring the 'druggability' of this attractive antimalarial target. A virtual screen followed by molecular docking with the PfAMA1 crystal structure was performed using an eight million compound collection that included commercial molecules, the ChEMBL malaria library and approved drugs. The consensus approach resulted in the selection of inhibitor candidates. We also developed a fluorescence anisotropy assay using a modified inhibitory peptide to experimentally validate the ability of the selected compounds to inhibit the AMA1-RON2 interaction. Among those, we identified one compound that displayed significant inhibition. This study offers interesting clues to improve the throughput and reliability of screening for new drug leads.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia-Antipolis, CNRS, UMR 7275, 660, Route des Lucioles, Sophia Antipolis, 06560, Valbonne, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Pihan
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Delgadillo
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Tonkin
authors.forename: Martine
authors.initials: M
authors.lastname: Pugnière
authors.forename: Maryse
authors.initials: M
authors.lastname: Lebrun
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Boulanger
authors.forename: Dominique
authors.initials: D
authors.lastname: Douguet
mesh_terms: D000595:Amino Acid Sequence; D000953:Antigens, Protozoan / Q000737:chemistry / Q000378:metabolism*; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D001703:Biophysics; D017076:Computer-Aided Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005454:Fluorescence Polarization; D020128:Inhibitory Concentration 50; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry; D020349:Surface Plasmon Resonance; D057188:Workflow
chemical_list: D000953:Antigens, Protozoan; D000962:Antimalarials; D008565:Membrane Proteins; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D054852:Small Molecule Libraries; C090077:apical membrane antigen I, Plasmodium