Molecular modeling and virtual screening for computer-aided design of plant protoporphyrinogen IX oxidase (PPO) inhibitors

• Inhibition of PPO is becoming increasingly essential due to the rising emergence of resistance to currently available herbicides. • Structural information from PPO-DPE complexes was used to create a quantitative structure-activity relationship (QSAR) and a pharmacophore models to predict PPO inhibition by DPE derivatives. • Newly designed analogues demonstrated low predicted inhibitory concentrations in the picomolar range. and their toxicity predictions indicated a lower risk for environmental and human health. • Molecular dynamics simulations (MDS) and MMGBSA calculations respectively confirm the stability and potency of the four most effectively designed analogues over a duration of 200 ns. • Four analogues are recommended for synthesis and evaluation of their bioactive activity to develop effective PPO-inhibiting herbicides. Protoporphyrinogen Oxidase IX (PPO) is a key target for agricultural herbicide design. In this study, we propose novel virtual PPO inhibitors using computer-aided 3D-QSAR combinatorial molecular design. Starting from the crystal structure of the PPO complex with a of fluazolate [4-Bromo-3-(5’-carboxy-4’-chloro-2’-fluorophenyl)-1-methyl-5-trifluoromethyl-pyrazol] (pdb code: 1SEZ), in situ modifications were made to generate first the 3D structure of the PPO-DPE1 complex and then a training set of sixteen (16) diphenyl ethers (DPE) with known experimental activities. A significant correlation was established between the relative Gibbs Free Energy (rGFE) of complex formation ( Δ Δ G c o m ) and the observed PPO inhibitory potency ( p I C 50 e x p ) , expressed as p I C 50 e x p = − 0.1735 Δ Δ G c o m + 7.902 , with R 2 = 0.96 . A 3D-QSAR pharmacophore (PH4) model, derived from active DPE conformations, was used to screen a virtual library of 161,051 compounds. The predictive robustness of PH4 ( p I C 50 e x p = 1.0077 p I C 50 p r e − 0.048 , R 2 = 0.81 ) , validated the selection of seventy (70) novel DPE analogues, with the most active exhibiting a predicted I C 50 p r e = 200 pM , 90 times more potent than DPE1 ( I C 50 e x p = 18 , 000 pM ) . Molecular dynamics simulations on the four (4) best predicted analogues and DPE1 confirmed the conformational stability of the PPO-DPE complexes, demonstrating the effectiveness of our approach.