Identifying novel selective PPO inhibitors through structure-based virtual screening and bio-evaluation.

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Protoporphyrinogen oxidase (PPO) is crucial for chlorophyll and heme synthesis.
• Current PPO inhibitors lack bio-selectivity, impacting non-target organisms.
• Developing selective PPO inhibitors is vital for pharmaceutical and pesticide applications.

Purpose of the Study:

• To identify novel selective PPO inhibitors using computational and experimental methods.
• To address the limitations of existing PPO inhibitors regarding bio-selectivity.
• To provide a basis for designing improved PPO inhibitors.

Main Methods:

• Docking-based virtual screening of chemical compounds.
• Bio-activity testing to evaluate inhibitor efficacy and selectivity.
• Molecular dynamics simulations to analyze selectivity mechanisms.

Main Results:

• Thirteen compounds exhibited at least 10-fold selectivity for non-human PPO over human PPO.
• Compound ZINC70338 demonstrated high selectivity (>113-fold) for *Nicotiana tabacum* PPO.
• Detailed analysis of ZINC70338's selectivity mechanism was performed.

Conclusions:

• Novel selective PPO inhibitors were successfully identified.
• ZINC70338 serves as a promising lead compound for developing safer PPO inhibitors.
• Molecular dynamics simulations offer insights into designing species-specific PPO inhibitors.