Structural and biophysical characterization of the Burkholderia pseudomallei IspF inhibitor L-tryptophan hydroxamate.

Autor: Blain JM; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Grote DL; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Watkins SM; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Goshu GM; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Muller C; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Gorman JL; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Ranieri G; Shamrock Structures LLC, 1440 Davey Rd, Woodridge, IL 60208, USA., Walter RL; Shamrock Structures LLC, 1440 Davey Rd, Woodridge, IL 60208, USA., Hofstetter H; Department of Chemistry, Univeristy of Wisconsin Madison, WI 53706, USA., Horn JR; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA. Electronic address: jrhorn@niu.edu., Hagen TJ; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA. Electronic address: thagen@niu.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Sep 15; Vol. 48, pp. 128273. Date of Electronic Publication: 2021 Jul 21.
DOI: 10.1016/j.bmcl.2021.128273
Abstrakt: The enzyme 2-methylerythritol 2,4-cyclodiphosphate synthase, IspF, is essential for the biosynthesis of isoprenoids in most bacteria, some eukaryotic parasites, and the plastids of plant cells. The development of inhibitors that target IspF may lead to novel classes of anti-infective agents or herbicides. Enantiomers of tryptophan hydroxamate were synthesized and evaluated for binding to Burkholderia pseudomallei (Bp) IspF. The L-isomer possessed the highest potency, binding BpIspF with a K D of 36 µM and inhibited BpIspF activity 55% at 120 µM. The high-resolution crystal structure of the L-tryptophan hydroxamate (3)/BpIspF complex revealed a non-traditional mode of hydroxamate binding where the ligand interacts with the active site zinc ion through the primary amine. In addition, two hydrogen bonds are formed with active site groups, and the indole group is buried within the hydrophobic pocket composed of side chains from the 60 s/70 s loop. Along with the co-crystal structure, STD NMR studies suggest the methylene group and indole ring are potential positions for optimization to enhance binding potency.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: