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Cyclobutanone Inhibitor Of Cobalt-Functionalized Metallo-Γ-Lactonase Aiia With Cyclobutanone Ring Opening In The Active Site, Cory T. Reidl, Romila Mascarenhas, Thahani S. Habeeb Mohammad, Marlon R. Lutz Jr, Pei W. Thomas, Walter Fast, Dali Liu, Daniel P. Becker Ph.D.

Chemistry: Faculty Publications and Other Works

An α-amido cyclobutanone possessing a C10 hydrocarbon tail was designed as a potential transition-state mimetic for the quorum-quenching metallo-γ-lactonase autoinducer inactivator A (AiiA) with the support of in-house modeling techniques and found to be a competitive inhibitor of dicobalt(II) AiiA with an inhibition constant of Ki = 0.007 ± 0.002 mM. The catalytic mechanism of AiiA was further explored using our product-based transition-state modeling (PBTSM) computational approach, providing substrate-intermediate models arising during enzyme turnover and further insight into substrate–enzyme interactions governing native substrate catalysis. These interactions were targeted in the docking of cyclobutanone hydrates into the active site of …