Affiliations: School of Chemical and Biotechnology, SASTRA
University, Thanjavur – 613 402, India | Vector Control Research Centre, Medical Complex,
Indira Nagar, Pondicherry – 605 006, India. E-mail: [email protected]
Abstract: The voltage-gated sodium channel (VGSC) is the target site for
insecticides such as DDT and synthetic pyrethroids. A single base (A-T) change
in the knock-down resistance (kdr) allele leads to an amino acid
substitution at position 267 that confers the target-mediated resistance to DDT
and synthetic pyrethroids in Anopheles gambiae. A theoretical model of
the VGSC domain II that contains the site of mutation was constructed using the
K^+ channel protein of Aeropyrum pernix as a template.
The validated model with 88.6% residues in the favored region was subjected
to the CASTp program that predicted 30 pockets in the modeled domain II for
ligand interaction. In the model, at position 267, leucine was manually
replaced with phenylalanine. When this altered model was subjected to the CASTp
program, the search results showed the same number of pockets. The docking
results indicate that DDT interacts with the modeled VGSC domain II at position
275 in the presence of leucine or in the presence of phenylalanine (binding
energy =−5.32 kcal/mol, −6.21 kcal/mol). It appears from the results that the
mutation at position 267 has no direct influence on the interaction of DDT with
the target protein. Therefore, to understand the interaction affinity of DDT
with the target and influence of the mutation on the existence of active
sites/pockets in relation to ligand binding, a whole VGSC model is
necessary.
