Przemyslaw Miszta, Subhash C. Basak, Ramanathan Natarajan and Wieslaw Nowak Pages 300 - 307 ( 8 )
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.
AgOR1, DEET, GPCR, malaria, mosquito repellents, VBD.
Institute of Physics, N. Copernicus University, ul. Grudziadzka 5, 87-100 Torun, Poland.