View article

Ebselen was previously found to potently inhibit the essential Mycobacterium tuberculosis (Mtb) Antigen 85s through the allosteric, covalent oxidation of a solvent exposed, conserved cysteine residue. In this study, we sought to better understand the in vitro inhibitory properties of a recently synthesized 1^st generation library of ebselen derivatives with respect to Ag85C. To better understand protein‐inhibitor interactions, Ag85C was successfully co‐crystalized with two bulky, chemically dissimilar derivatives, resulting in two X‐ray crystal structures of 2.01 Å and 1.30 Å. Both inhibitors displayed an aromatic stacking interaction with Phe253 and the aromatic ring of the ebselen scaffold in addition to a cationic interaction between the side chain of Arg239 and the respective chemical derivative. Aside from these interactions with Ag85C, the ebselen derivative was oriented towards solvent. To better understand how these …