Computational and biophysical approaches to protein–protein interaction inhibition of Plasmodium falciparum AMA1/RON2 complex

Autor: Roberto F. Delgadillo, Maryse Lebrun, Martine Pugnière, Michelle L. Tonkin, Dominique Douguet, Martin J. Boulanger, Emilie Pihan
Přispěvatelé: Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), University of Victoria [Canada] (UVIC), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2015
Předmět:
Molecular Sequence Data
Biophysics
Drug Evaluation
Preclinical
Protozoan Proteins
Druggability
Antigens
Protozoan
Fluorescence Polarization
Receptors
Cell Surface
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
Biology
Molecular Docking Simulation
Workflow
Protein–protein interaction
Small Molecule Libraries
Antimalarials
Inhibitory Concentration 50
Drug Discovery
Amino Acid Sequence
Physical and Theoretical Chemistry
Apical membrane antigen 1
Peptide sequence
ComputingMilieux_MISCELLANEOUS
Virtual screening
Membrane Proteins
Reproducibility of Results
Plasmodium falciparum
[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
Surface Plasmon Resonance
biology.organism_classification
3. Good health
Computer Science Applications
Rhoptry neck
Biochemistry
Immunology
Computer-Aided Design
[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
[CHIM.CHEM]Chemical Sciences/Cheminformatics
Zdroj: Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design, Springer Verlag, 2015, 29 (6), pp.525-539. ⟨10.1007/s10822-015-9842-7⟩
ISSN: 1573-4951
0920-654X
DOI: 10.1007/s10822-015-9842-7
Popis: 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 local- ized to the apical surface that coordinates RON2 and invasion inhibitory peptides. In the present work, we em- ployed 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 se- lected 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.
Databáze: OpenAIRE
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