In silico ligand self-assembly drives binding recognition of natural products into Anopheles gambiae cytosolic sulfotransferases (AgSULT-001425) protein.

Abstract

Malaria remains one of the most devastating diseases affecting humanity, generating a significant interest in developing effective and reliable interventions. Synthetic insecticides widely used for vector control face limitations due to increased insect resistance and toxicity to humans and non-target species. Indole alkaloids, recognized for their insecticidal properties, have emerged as promising alternatives, however, their molecular mechanisms and efficacy for malaria vector control have not been fully explored or documented. AgSULT-001425, a sulfotransferase enzyme crucial for mosquito development and reproductive success, represents a key target for disrupting mosquito survival. To investigate this, molecular docking, dynamics, and MMPBSA analyses were employed to explore the binding mechanisms, stability, and self-assembly of indole alkaloids with AgSULT-001425. The binding affinity was ranked as EP4 > ST6 > AS4 > SP4. Hydrated docking indicated that EP4-7R0U binding affinity improved significantly to - 10.41 kcal/mol, surpassing the binding affinity of the co-crystallized ligand by - 1.0 kcal/mol. ADME/T analysis confirmed drug-like properties and high bioavailability with adherence to Lipinski's rule of five. Stability analyses demonstrated minimal structural deviations, compact protein structures ensuring stable interactions. MMPBSA identified EP4 (- 94.83 kJ/mol) and ST6 (- 91.67 kJ/mol) as exhibiting the strongest binding energies. During self-assembly, SP4 achieved the shortest distance to the protein, whereas the free energy surface emphasized stable interactions for both EP4 and SP4. Based on these findings, the identified natural inhibitors demonstrate potential as lead compounds for developing more potent insecticides. However, experimental validation is needed to confirm their efficacy and optimize their properties for practical use.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00403-8.