In silico strategies for discovering and analyzing new molecules based on isocycloseram: Virtual screening, docking, molecular dynamics, MM/PBSA, and GABA receptor interactions

The agricultural insecticide market is becoming increasingly competitive. With the launch of PLINAZOLIN® Technology, significant attention has been given to its active ingredient, Isocycloseram, which is effective across more than 40 plant crops. However, there are already reports of resistance development to this insecticide. Given this scenario, the search for new molecules that act similarly to Isocycloseram in controlling various pests is essential. However, the discovery and development of new molecules can take years and require substantial financial investment. A useful and efficient alternative is applying in silico methods to accelerate the discovery of new active ingredients, making the development process shorter and more cost-effective. In this context, this study aimed to apply in silico methods to identify new active ingredients with pharmacophoric groups similar to those of Isocycloseram, given its relevant applications in various plant crops. To achieve this, virtual screening was performed on eight molecular databases, comprising over 215 million compounds, to identify new molecules of interest. Subsequently, multiple filtering steps were applied to ensure that only the best-ranked compounds were selected. Since the three-dimensional structure of the GABA receptor, the molecular target of Isocycloseram, is unavailable, homology modeling was conducted, along with validation of the generated model. Additionally, docking simulations, molecular dynamics, MM/PBSA calculations, and various analyses were performed. Overall, this study presents a novel approach using in silico methods to identify desirable active ingredients and provides two new molecules that could enhance market competition against Isocycloseram, thereby expanding the portfolio of agricultural insecticides.