Deciphering the Selectivity and Reactivity of Ebselen Derivatives toward Mycobacterium tuberculosis Antigen 85C

• DOI: 10.1096/fasebj.31.1_supplement.921.14
• Publication Date: 2023-11-26T17:29:50Z
• Authors: Christopher M Goins; Steven Dajnowicz; Sandeep Thanna; Steven J Sucheck; Jerry M Parks; Donald R Ronning
• Keywords: Ebselen; Reactivity

Ebselen was previously found to potently inhibit the essential Mycobacterium tuberculosis ( Mtb ) Antigen 85s through allosteric, covalent oxidation of a solvent exposed, conserved cysteine residue. In this study, we sought better understand in vitro inhibitory properties recently synthesized 1 st generation library ebselen derivatives with respect Ag85C. To protein‐inhibitor interactions, Ag85C successfully co‐crystalized two bulky, chemically dissimilar derivatives, resulting X‐ray crystal structures 2.01 Å and 1.30 Å. Both inhibitors displayed an aromatic stacking interaction Phe253 ring scaffold addition cationic between side chain Arg239 respective chemical derivative. Aside from these interactions Ag85C, derivative oriented towards solvent. how potentially facilitate initial drug binding, unique various energetics were computed for both using Density Functional Theory. When comparing energetic values activities, capable forming favorable have higher levels inhibition. Furthermore, looked into electronic effects on reactivity selenium Cys209 The little too no effect reactivity, strengthening importance Arg239. novel greater shift movement helix α9 than what observed previous structure. This caused elongation restructuring loop connecting preceding β‐strand. We questioned whether affected protein stability differential scanning fluorimetry that modified by or its decreased melting temperature 14 °C. results unfolding at physiological temperatures. Upon closer inspection structures, channel leading active site is observable. great intrigue us as future path development Ag85s. Support Funding Information NIH grant AI105084