In Silico Evaluation and Simulation-Based Prioritization of Herbicide-like Compounds Targeting Phalaris minor Acetyl-CoA Carboxylase

Phalaris minor, a notorious weed commonly found in wheat fields, exhibits an aggressive growth rate that makes it a persistent threat to wheat crops. Complicating matters, the weed and wheat share phenotypic similarities during their early growth stages, making manual weeding challenging. As a result, herbicide application has become the primary method for controlling P. minor infestations. However, the excessive use of herbicides has led to the evolution of resistant P. minor biotypes, rendering many commercially available herbicides less effective. This pressing issue underscores the need for developing novel herbicides, which are the central focus of our study. A computational structure-based virtual screening approach has been employed on ZINC15, CHEMBL, and DrugBank databases to identify herbicide-like compounds. The filtered candidates have been evaluated for their binding affinity, benchmarked against the widely used herbicides diclofop (aryloxyphenoxypropionates, i.e., FOP) and tepraloxydim (cyclohexanediones, i.e., DIM), which have inhibiting activity against acetyl-CoA carboxylase (ACCase). Subsequently, molecular dynamics simulations for 100 ns were conducted on the filtered compounds complexed with the modeled ACCase protein of P. minor. Simulated trajectory analysis revealed the interaction dynamics and stability of the selected candidate compounds (CID 44331977, CID 118061654, CID 25783158, and CID 136016466). Simulated trajectories have also been analyzed for their binding free energies to stipulate the stability and strength of interactions. A deeper insight into the dynamics of simulated complex principal component analysis of the trajectories has been analyzed followed by mapping of Gibbs free energy on the free energy landscape plot, which ensured the stability of selected molecules. The in silico analysis proved these compounds possess herbicide-like properties with possible activity against the ACCase protein of P. minor.