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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:48

Article

Blain, Joy M.¹  Grote, Dakota L.¹  Watkins, Sydney M.¹  Goshu, Gashaw M.¹  Muller, Chante¹  Gorman, James L.¹  Ranieri, Gina^2,4  Walter, Richard L.^2,5  Hofstetter, Heike³  Horn, James R.¹  Hagen, Timothy J.¹ 

[1] Northern Illinois Univ, Dept Chem & Biochem, 1425 W Lincoln Hwy, De Kalb, IL 60115 USA

[2] Shamrock Struct LLC, 1440 Davey Rd, Woodridge, IL 60208 USA

[3] Univ Wisconsin, Dept Chem, 1101 Univ Ave, Madison, WI 53706 USA

[4] Procter & Gamble Co, 1 P&G Plaza, Cincinnati, OH 45202 USA

[5] XTALPAC LLC, 361 N Raynor Ave, Joliet, IL 60435 USA

关键词: IspF;    MEP pathway;    Burkholderia pseudomallei;    Binding thermodynamics;    Isothermal titration calorimetry;    X-ray Crystallography;   

DOI  :  10.1016/j.bmcl.2021.128273

来源: Elsevier

【 摘 要 】

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 KD of 36 mu M and inhibited BpIspF activity 55% at 120 mu M. 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.

【 授权许可】

Free