Abstract: 【Aim】 To screen potential inhibitors targeting kynurenine formamidase (KFase) of Anopheles gambiae, which could be a candidate insecticide to reduce malaria transmission, by virtual screening. 【Methods】 Protein sequences homologous with KFase of An. gambiae were searched and downloaded from NCBI using BLASTP web server. Phylogenetic tree of homologous proteins was constructed by MEGA6 using maximum likelihood method. Homology modeling of KFase of An. gambiae was performed by SWISS-MODEL web server using KFase of Drosophila melanogaster (PDB ID: 4E14) as a template. The small-molecule compounds were downloaded from ZINC database and then screened by the method of random forest. Docking analysis of the homology model and selected small molecule compounds was carried out, and the screening results were further validated using molecular dynamics simulation. 【Results】 Three small-molecule compounds, i.e., N-(2,4-diketo-1H-pyrimidin-6-yl)-2-fluoro-benzamide, 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid, and N-(2-oxo-2, 3-dihydro-1H-imidazo［4, 5-b］ pyridin-5-yl)-succinamic acid, have the lowest docking energy to KFase of An. gambiae with the affinity energy of -9.0, -8.7 and -8.9 kcal/mol, respectively. 【Conclusion】 The three small-molecule compounds, i.e., N-(2,4-diketo-1H-pyrimidin-6-yl)-2-fluoro-benzamide, 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid, and N-(2-oxo-2, 3-dihydro-1H-imidazo［4, 5-b］ pyridin-5-yl)-succinamic acid, could be candidate competitive inhibitors of KFase of An. gambiae. Whether these compounds can be used as candidate mosquitocides needs further experimental validation.

Key words: Anopheles gambiae, malaria, kynurenine formamidase, inhibitor, virtual screening, random forest, bioinformatics