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Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase Pf A‐M1
Author(s) -
Yang Wei,
Riley Blake T.,
Lei Xiangyun,
Porebski Benjamin T.,
Kass Itamar,
Buckle Ashley M.,
McGowan Sheena
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800563
Subject(s) - aminopeptidase , molecular dynamics , active site , plasmodium falciparum , computational biology , enzyme , chemistry , biology , stereochemistry , biochemistry , biophysics , leucine , amino acid , computational chemistry , malaria , immunology
The M1 metallo‐aminopeptidase from Plasmodium falciparum, Pf A‐M1, is an attractive drug target for the design of new antimalarials. Bestatin, a broad‐spectrum metalloprotease inhibitor, is a moderate inhibitor of Pf A‐M1, and has been used to provide structure–activity relationships to inform drug design. The crystal structure of Pf A‐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 Pf A‐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.