Biology

Small molecule

Isoxazole

Biochemistry

Molecule

Computational biology

Stereochemistry

Genetics

Combinatorial chemistry

Organic chemistry

Structure–activity relationship

Pyrazole

In vitro

Enzyme

Rational design

Chemistry

Dioxygenase

Amide

Advanced Agrochem

4-Hydrophenylpyruvate dioxygenase (HPPD), a key enzyme involved in tyrosine catabolism, has long been considered a promising target for herbicides and drugs. Several types of HPPD inhibitors have been developed as high-potency drugs or herbicides. Understanding the structural basis of the binding of these inhibitors with HPPD will be beneficial for the development of inhibitors containing novel scaffolds. However, only limited structural information regarding the binding of triketone and pyrazole derivatives with HPPD has been reported. Here, the crystal structures of HPPD complexed with inhibitors containing different scaffolds, including triketone, pyrazole, isoxazole, heterocyclic amide, and quinazolindione derivatives, were comprehensively analyzed. Detailed binding modes of isoxazole and heterocyclic amide derivatives with HPPD were first revealed, facilitating further structural optimization. The binding mode of compound 2 with HPPD suggests that both oxygen and nitrogen atoms can mediate coordination with the metal ion. These results will provide the structure-based rational design of novel HPPD inhibitors.

Structural insights of 4-Hydrophenylpyruvate dioxygenase inhibition by structurally diverse small molecules