An Oxyprenylated Phenylpropanoid Pharmacologic Scaffold for SelU Inhibition

A small library of natural oxyprenylated phenylpropanoids is investigated as potential inhibitors of tRNA 2-selenouridine synthase (MnmH, also called SelU), a member of the Mnm family of enzymes that modify uridine at the wobble position of specific tRNAs. Screening each compound against the N-terminal domain of SelU via fluorescence quenching methodology reveals details of substrate binding mode and conformational flexibility of this enzyme.

MnmH, better known as tRNA 2-selenouridine synthase (SelU), is a member of the Mnm family enzymes that work in concert to modify uridine at the wobble position. Instrumental in maintaining base pair fidelity and exclusive to bacteria, SelU is a promising drug target. Although no molecular structure has been experimentally calculated, insights into this enzyme's mechanism of catalysis have been empirically gleaned and proven useful for ligand-based rational drug design. In this study, a small group of natural and semisynthetic oxyprenylated phenylpropanoids were selected based on their compositional resemblance to the purported SelU ligands. Specifically, these compounds contained one or more geranyl groups branching from aromatic frameworks, all of which are believed to heighten affinity to SelU. Meticulous screening of each compound against an N-terminal SelU construct via fluorescence quenching of W83 further reveals details on the enzyme-substrate binding mode. Conformational flexibility of residues around W83 is suggested by the slow bimolecular quenching constants calculated for each compound. This is consistent with the single binding site and the blend of interaction-types calculated at the active site. Lastly, this general oxyprenylated framework, along with a cinnamic acid moiety, is established as a pharmacologic scaffold that can be further optimized into potential antibiotics.

Zum Volltext