title: How computational studies of mosquito repellents contribute to the control of vector Borne Diseases.
abstract: Vector Borne Diseases (VBD) present a serious threat to millions of people. In this paper various computational approaches towards new drugs design against some of them are reviewed. Malaria attracts particular attention of computational medicinal chemists. A promising strategy of the fight with VBD is usage of insect repellents. N,N-Diethyl-m-toluamide (DEET) has been the mostly used mosquito repellent for over five decades. Its mode of action is still a matter of intensive studies and debate. A possible mechanism of DEET activity is inactivation of odorant receptor proteins expressed in female mosquitoes, and being critical for finding a prey. In order to check possible interactions of DEET with such a transmembrane protein and to indicate a plausible biophore, we have constructed a hybrid "ab initio" model of Anopheles gambiae Odorant Receptor Protein 1 (AgOR1). The transmembrane regions of AgOR1 were predicted using 10 different bioinformatics algorithms and a consensus approach. A full torsional potential energy surface of DEET was determined using the AM1 method and low energy conformers were further optimized using the HF/6-31G method. DEET and a series of diastereomers of alternative repellent cyclohex-3-enyl 2-methylpiperidin-1-yl ketone (220) was docked to the AgOR1 model using the AutoDock 3.0.5 code, and possible interactions sites inside this GPCR AgOR1 were identified.
authors.affiliation: Institute of Physics, N. Copernicus University, ul. Grudziadzka 5, 87-100 Torun, Poland. wiesiek@fizyka.umk.pl
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Miszta
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Basak
authors.forename: Ramanathan
authors.initials: R
authors.lastname: Natarajan
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Nowak
mesh_terms: D000818:Animals; D000852:Anopheles / Q000187:drug effects* / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D017076:Computer-Aided Design; D003671:DEET / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D019476:Insect Proteins / Q000737:chemistry / Q000378:metabolism; D007302:Insect Repellents / Q000737:chemistry / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy* / Q000635:transmission; D062105:Molecular Docking Simulation; D018035:Receptors, Odorant / Q000737:chemistry / Q000378:metabolism
chemical_list: D000962:Antimalarials; D019476:Insect Proteins; D007302:Insect Repellents; D018035:Receptors, Odorant; D003671:DEET