Virtual screening based on pharmacophore model for developing novel HPPD inhibitors.
Pestic Biochem Physiol
; 184: 105109, 2022 Jun.
Article
in En
| MEDLINE
| ID: mdl-35715048
ABSTRACT
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for herbicide design. A multilayered virtual screening workflow was constructed by combining two pharmacophore models based on ligand and crystal complexes, molecular docking, molecular dynamics (MD), and biological activity determination to identify novel small-molecule inhibitors of HPPD. About 110, 000 compounds of Bailingwei and traditional Chinese medicine databases were screened. Of these, 333 were analyzed through docking experiments. Five compounds were selected by analyzing the binding pattern of inhibitors with amino acid residues in the active pocket. All five compounds could produce stable coordination with cobalt ion, and form favorable π-π interactions. MD simulation demonstrated that Phe381 and Phe424 made large contributions to the strength of binding. The enzyme activity experiment verified that compound-139 displayed excellent potency against AtHPPD (IC50 = 0.742 µM), however, compound-5222 had inhibitory effect on human HPPD (IC50 = 6 nM). Compound-139 exhibited herbicidal activity to some extent on different gramineous weeds. This work provided a strong insight into the design and development of novel HPPD inhibitor using in silico techniques.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Herbicides
/
4-Hydroxyphenylpyruvate Dioxygenase
Type of study:
Diagnostic_studies
/
Screening_studies
Language:
En
Journal:
Pestic Biochem Physiol
Year:
2022
Document type:
Article
Affiliation country:
China