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Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase PfA-M1.
Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase PfA-M1.
- Source :
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ChemMedChem [ChemMedChem] 2018 Dec 06; Vol. 13 (23), pp. 2504-2513. Date of Electronic Publication: 2018 Nov 09. - Publication Year :
- 2018
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Abstract
- The M1 metallo-aminopeptidase from Plasmodium falciparum, PfA-M1, is an attractive drug target for the design of new antimalarials. Bestatin, a broad-spectrum metalloprotease inhibitor, is a moderate inhibitor of PfA-M1, and has been used to provide structure-activity relationships to inform drug design. The crystal structure of PfA-M1 with bestatin bound within its active site has been determined; however, dynamics of the inhibitor and the association or dissociation pathway have yet to be characterized. Here we present an all-atom molecular dynamics study where we have generated a hidden Markov state model from 2.3 μs of molecular dynamics simulation. Our hidden Markov state model identifies five macrostates that clearly show the events involved in bestatin dissociation from the PfA-M1 active site. The results show for the first time that bestatin can escape the substrate specificity pockets of the enzyme, primarily due to weak interactions within the pockets. Our approach identifies relevant conformational sampling of the inhibitor inside the enzyme and the protein dynamics that could be exploited to produce potent and selective inhibitors that can differentiate between similar members of the M1 aminopeptidase superfamily.<br /> (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Aminopeptidases chemistry
Aminopeptidases metabolism
Catalytic Domain drug effects
Drug Discovery
Humans
Leucine pharmacology
Malaria, Falciparum drug therapy
Malaria, Falciparum parasitology
Molecular Docking Simulation
Molecular Dynamics Simulation
Plasmodium falciparum chemistry
Plasmodium falciparum drug effects
Plasmodium falciparum metabolism
Protein Binding
Aminopeptidases antagonists & inhibitors
Antimalarials pharmacology
Enzyme Inhibitors pharmacology
Leucine analogs & derivatives
Plasmodium falciparum enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 13
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 30318749
- Full Text :
- https://doi.org/10.1002/cmdc.201800563