title: Molecular docking and simulation studies of gustatory receptor of Aedes aegypti: A potent drug target to distract host-seeking behaviour in mosquitoes.
abstract: OBJECTIVE
  It is well reported that exhaled CO 2 and skin odour from human being assist female mosquitoes to locate human host. Basically, the receptors for this activity are expressed in cpA neurons. In both Aedes aegypti and Anopheles gambiae, this CO 2-sensitive olfactory neuron detects myriad number of chemicals present in human skin. Therefore, manipulation of gustatory receptors housing these neurons may serve as important targets for behavioural intervention. The study was aimed towards virtual screening of small molecules in the analyzed conserved active site residues of gustatory receptor and molecular dynamics simulation study of optimum protein-ligand complex to identify a suitable lead molecule for distracting host-seeking behaviour of mosquitoes.
  
  
  METHODS
  The conserved residue analysis of gustatory receptor (GR) of Ae. aegypti and An. gambiae was performed. The structure of GR protein from Ae. aegypti was modeled and validated, and then molecular docking was performed to screen 2903 small molecules against the predicted active residues of GR. Further, simulation studies were also carried out to prove protein-ligand stability.
  
  
  RESULTS
  The glutamine 154 residue of GR was found to be highly conserved in Ae. aegypti and An. gambiae. Docking results indicated that the dodecanoic acid, 1,2,3-propanetriyl ester (dynasan 112) was interacting with this residue, as it showed better LibDock score than previously reported ethyl acetate used as mosquito repellant. Simulation studies indicated the structural instability of GR protein in docked form with dynasan 112 suggesting its involvement in structural changes. Based on the interaction energies and stability, this compound has been proposed to be used in mosquitoes' repellant.
  
  
  CONCLUSIONS
  A novel effective odorant acting as inhibitor of GR is proposed based on its stability, docking score, interactions and RMSD, considering ethyl pyruvate as a standard inhibitor. Host preference and host-seeking ability of mosquito vectors play key roles in disease transmission, a clear understanding of these aspects is essential for preventing the spread of the disease.
authors.affiliation: Centre for Bioinformatics, Pondicherry University, Puducherry, India.
authors.forename: Krishna Kant
authors.initials: KK
authors.lastname: Gupta
authors.affiliation: Centre for Bioinformatics, Pondicherry University, Puducherry, India.
authors.forename: Guneswar
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Centre for Bioinformatics, Pondicherry University, Puducherry, India.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Jayaraman
mesh_terms: D000330:Aedes / Q000737:chemistry*; D000818:Animals; D000852:Anopheles / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D019476:Insect Proteins / Q000737:chemistry* / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009812:Odorants; D010575:Pesticides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D019476:Insect Proteins; D010575:Pesticides; D011956:Receptors, Cell Surface