A hierarchical in silico screening of Streptomyces-derived natural products to identify novel inhibitors of the Bemisia tabaci ecdysone receptor (EcR)

The whitefly Bemisia tabaci is a devastating global agricultural pest that has developed growing resistance to conventional insecticides. Targeting the insect-specific ecdysone receptor (EcR) offers a promising strategy for developing selective and sustainable pesticides. This study employed a rigorous hierarchical virtual screening workflow on 6,524 Streptomyces-derived natural compounds, integrating molecular docking, ADMET filtering, extensive 100 ns molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, and principal component analysis (PCA). Our analysis revealed a critical disconnect between initial docking scores and long-term dynamic stability: compounds with high docking affinities often proved unstable in simulation, while two compounds, Solphenazine E and an Acetamide derivative emerged as stable binders based on MD simulations and predicted interaction patterns. Both maintained persistent hydrogen bonding with the critical residue ARG97, exhibited robust RMSD profiles comparable to the co-crystal control, and demonstrated strong binding free energies (ΔG = −56.05 and −55.38 kcal/mol, respectively). In contrast, while 16α-hydroxyestrone displayed the most favorable ADMET safety profile (non-mutagenic, non-hepatotoxic), its weak binding energy (ΔG = −37.86 kcal/mol), high ligand mobility (RMSD >3 Å after 40 ns), and intermittent ARG97 interactions disqualified it as a primary candidate despite its lower predicted human toxicity. This study demonstrates that Solphenazine E and the Acetamide derivative are dynamically stable, computationally predicted insecticide-selective EcR inhibitors, and identifies them as the most promising natural product leads for targeted pest control of B. tabaci. Our findings underscore the necessity of multi-tiered computational validation and demonstrate that ADMET favorability, while important for human safety, must be weighed against binding stability and efficacy for insecticidal application. Future development should focus on experimental validation of these stable binders, with formulation and exposure control strategies to mitigate any off-target hepatotoxicity concerns.