Structural Optimization for 4-hydroxyphenylpyruvate Dioxygenase Inhibitors Based on 3D-QSAR, Molecular Docking, SBP Modeling and MOLCAD Studies

Background: The research based on natural product herbicides has been increasingly attractive in the field of agriculture. 4-hydroxyphenylpyruvate dioxygenase (HPPD) is one of the most promising compounds in the field of herbicide innovation. Objective: This paper aims to study the relationship between the activity and structure of quinazoline- 2,4-dione derivatives, and to design novel HPPD inhibitors. Methods: A set of quinazoline-2,4-dione derivatives underwent 3D-QSAR studies as well as molecular docking. MOLCAD analysis and 8-point pharmacophore model provided an important reference for us to understand the interaction mode of HPPD and antagonists. Results: The CoMFA (n = 5; q² = 0.778; r² = 0.985) and CoMSIA (n = 6; q² = 0.776; r² = 0.95) models had remarkable stability and predictability. MOLCAD studies and pharmacophore modeling proved the validity of the 3D-QSAR model. On the basis of the gained information, nine novel derivatives as potential candidates of HPPD inhibitors with better predicted activities were designed, mainly binding to HPPD via lipophilic interaction and hydrogen bonding. The key hydrophobic residues of HPPD, Phe381, His308, Asn282, Phe392 and Leu368, were found to be antagonist binding sites that are important factors for the stability of the antagonist binding site. Conclusion: The structural basis and activity of HPPD inhibitors were revealed, which might provide clear and solid insights to guide the rational design of novel HPPD inhibitors.