In Silico analysis of voltage-gated sodium channel in relation to DDT resistance in vector mosquitoes.

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.

Structure of glutathione S-transferase of the filarial parasite Wuchereria bancrofti: a target for drug development against adult worm.

A three dimensional structural model of Glutathione-S-transferase (GST) of the lymphatic filarial parasite Wuchereria bancrofti (wb) was constructed by homology modeling. The three dimensional X-ray crystal structure of porcine pi-class GST with PDB ID: 2gsr-A chain protein with 42% sequential and functional homology was used as the template. The model of wbGST built by MODELLER6v2 was analyzed by the PROCHECK programs. Ramachandran plot analysis showed that 93.5% of the residues are in the core region followed by 5.4 and 1.1% residues in the allowed and generously allowed regions, respectively. None of the non-glycine residues is in disallowed regions. The PROSA II z-score and the energy graph for the final model further confirmed the quality of the modeled structure. The computationally modeled three-dimensional (3D) structure of wbGST has been submitted to the Protein Data Bank (PDB) (PDB ID: 1SFM and RCSB ID: RCSB021668). 1SFM was used for docking with GST inhibitors by Hex4.2 macromolecular docking using spherical polar Fourier correlations.