Functionally Improved Urease Inhibitors (NBPT): Developed Approaches for Obtaining Environmentally Friendly Derivatives

Traditional agricultural urease inhibitors encounter a low inhibition efficiency and a short duration of action. Therefore, the typical traditional urease inhibitor n-butylthiophosphoric acid triamide (NBPT) was modified by molecular docking and molecular dynamics and combined with machine learning methods in this study. Seven out of 79 designed urease inhibitor substitutes were screened with improved urease inhibition potential of 21.30–48.91% compared with NBPT. After using the improved G1 evaluation method, four were selected as alternative urease inhibitor substitutes, with a reduction of 22.30–47.40% and an increase of 25.30–47.71% in soil toxicity and the urease inhibition potential, respectively. In addition, through simulation of functional properties, it was found that the alternatives were expected to reduce ammonia volatilization rate by 65.16–76.81% and N2O emissions by 30.53–57.60% after application, and the soil half-life was 2.5 times that of NBPT. Mechanistic analysis of protein–ligand interactions revealed that the number of hydrogen bonds and π–π stacking interactions are the primary intrinsic factors driving the improved urease inhibition of the substitute molecules. This study provides a new solution for reducing nitrogen loss, lowering greenhouse gas emissions, alleviating agricultural nonpoint source pollution, and promoting the research and development of green fertilizers.