Noncovalent interactions between quinoxalines and protoporphyrinogen oxidase (PPO): a computational case study for herbicidal applications

Quinoxaline-based compounds show promising inhibition of protoporphyrinogen oxidase (PPO), a key enzyme in chlorophyll production and a prime target for herbicide development. However, their precise molecular interactions remain largely unexplored. This study investigates 1-propyl-3-phenylquinoxalin-2(1H)-one (Qnz), a novel quinoxaline derivative designed and synthesized as a representative system. We examined its interaction, at the atomic level, with the active site of Nicotiana tabacum PPO (NtPPO) using an integrated molecular docking and DFT-based quantum mechanics cluster approach. The nature and strength of observed noncovalent interactions were theoretically evaluated using quantum theory of atoms-in-molecules (QTAIM), independent gradient model (IGM), and natural bond orbital (NBO) methods. Our analysis revealed a fascinating set of unconventional interactions that contribute to the stability of the Qnz–NtPPO complex, namely weak hydrogen bonding, homopolar dihydrogen interactions, π–stacking, and carbonyl–carbonyl interactions. Interestingly, the study uncovered the unexpected role of several less common amino acids—including Gly178, Ser235, and nonpolar aliphatic leucines—in facilitating molecular recognition. Moreover, the employed computational approaches have proven to be a powerful tool for analyzing interactions within the binding pocket.