Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase PfA‐M1. (9th November 2018)

• Record Type: Journal Article
• Authors: Yang, Wei; Riley, Blake T.; Lei, Xiangyun; Porebski, Benjamin T.; Kass, Itamar; Buckle, Ashley M.; McGowan, Sheena
• Is Part Of: ChemMedChem. Volume 13:Number 23(2018)
• Page Start: 2504
• Page End: 2513
• Publication Date: 2018-11-09
• Subjects: bestatin -- M1 aminopeptidase -- Markov models -- molecular dynamics -- molecular mechanisms; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800563
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : Motion picture release : X‐ray crystallographic analyses of inhibitor‐bound drug candidates is a static "snapshot" of the final bound state, but provides little information on the events before or after association. What is essentially needed is a "movie" that describes how the inhibitor engages and disengages with its target. Here, using simulation techniques, we map the route by which the inhibitor bestatin can dissociate from the Plasmodium falciparum M1 aminopeptidase.