Scaffold-Hunting From Pyriproxyfen: A Biochemoinformatic Route to Novel Insecticidal Leads.

Vector-borne diseases remain a critical global health concern, particularly in tropical and subtropical regions, where socioeconomic conditions often favor vector proliferation. Pyriproxyfen, a juvenile hormone analog used as a larvicide against Aedes aegypti, is known for its fast-acting efficacy, low toxicity, and favorable environmental profile. Because of these properties, pyriproxyfen was chosen as a reference scaffold to explore structurally and electrostatically similar compounds through ligand-based virtual screening. The ChemBridge DIVERSet-CL database (≈ 100,000 compounds) was used, applying ROCS for shape similarity and EON for electrostatic potential comparison. A total of 35 top-ranked molecules were identified based on superior pharmacokinetic and toxicological properties compared with the reference. Subsequently, molecular docking analyses were performed to assess binding affinity and interaction modes with selected biological targets: acetylcholinesterase (AChE) and juvenile hormone-binding proteins from various organisms. Two compounds, LMQC3 and LMQC23, demonstrated strong binding affinities to AChE enzymes from Drosophila melanogaster (-11.4 and -10.6 kcal/mol), Anopheles gambiae (-10.19 and -10.21 kcal/mol), and humans (-9.91 and -9.95 kcal/mol). Additionally, they exhibited high affinity toward the juvenile hormone protein in A. aegypti (-11.83 and -11.94 kcal/mol), surpassing reference ligands. Both molecules established key interactions with catalytic residues, supporting their potential dual inhibitory activity. These findings indicate that LMQC3 and LMQC23 are potential promising insecticidal candidates with multitarget potential, showing favorable predicted target-binding profiles and encouraging in silico pharmacokinetic and toxicity characteristics. Their development could contribute to next-generation mosquito control strategies and help mitigate the spread of arbovirus-related diseases.