In silico models for predicting vector control chemicals targeting Aedes aegypti

Abstract

Human arboviral diseases have emerged or re-emerged in numerous countries worldwide due to a number of factors including the lack of progress in vaccine development, lack of drugs, insecticide resistance in mosquitoes, climate changes, societal behaviours, and economical constraints. Thus, Aedes aegypti is the main vector of the yellow fever and dengue fever flaviviruses and is also responsible for several recent outbreaks of the chikungunya alphavirus. As for the other mosquito species, the A. aegypti control relies heavily on the use of insecticides. However, because of increasing resistance to the different families of insecticides, reduction of Aedes populations is becoming increasingly difficult. Despite the unquestionable utility of insecticides in fighting mosquito populations, there are very few new insecticides developed and commercialized for vector control. This is because the high cost of the discovery of an insecticide is not counterbalanced by the 'low profitability' of the vector control market. Fortunately, the use of quantitative structure-activity relationship (QSAR) modelling allows the reduction of time and cost in the discovery of new chemical structures potentially active against mosquitoes. In this context, the goal of the present study was to review all the existing QSAR models on A. aegypti. The homology and pharmacophore models were also reviewed. Specific attention was paid to show the variety of targets investigated in Aedes in relation to the physiology and ecology of the mosquito as well as the diversity of the chemical structures which have been proposed, encompassing man-made and natural substances.

Keywords: Aedes aegypti; QSAR; adulticide; homology modelling; larvicide.

Figure 1.

Structure of 20-hydroxyecdysone.

Figure 2.

Structure of juvenile hormone III (JH3), hydroprene, kinoprene, methoprene, pyriproxyfen, and fenoxycarb.

Figure 3.

2,4-dodecadienone skeleton. X = OR, SR, NHR, NR2, Alkyl; R₁ = H, OR, SEt, 10-ene, 11-ene, 10-epoxy, oxo; Y = OR, SR, OCOR, Me, Et; R₂ = H, Me, Cl.

Figure 4.

Structure of tebufenozide.

Figure 5.

Structure of triorganotin 2,2,3,3-tetramethylcyclopropanecarboxylates (left), triphenyltin para-substituted benzoates (middle), and tricyclohexyltin para-substituted benzoates (right).

Figure 6.

Structure of alantolactone and isoalantolactone.

Figure 7.

Structure of methyl vilangin, embelin, and myrsinone.

Figure 8.

Structure of eugenol, geraniol, coumarin, eucalyptol, and carvacrol.

Figure 9.

Structure of dillapiol (left) and isodillapiol (right).

Figure 10.

Structure of 1-nonanoyl-2-ethyl-piperidine (left) and 1-octanoyl-3-benzyl-piperidine (right).

Figure 11.

SIRIS map of the 129 insecticides used or potentially usable as larvicides (See text for the correspondence between some numbers and chemical names).

Figure 12.

Structure of amitriptyline and doxepin.

Figure 13.

Structure of cis-(z)-flupenthixol and chlorpromazine.

Figure 14.

Example of triazine very active against A. aegypti.

Figure 15.

Structure of GCA-18.

Figure 16.

Chemicals predicted as binders to A. aegypti chorion peroxidase.