Gupta Krishna Kant, Sethi Guneswar, Jayaraman Manikandan
Centre for Bioinformatics, Pondicherry University, Puducherry, India.
J Vector Borne Dis. 2016 Apr-Jun;53(2):179-84.
BACKGROUND & OBJECTIVES: 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.
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.
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.
INTERPRETATION & CONCLUSION: 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.
有充分报道表明，人类呼出的二氧化碳和皮肤气味有助于雌性蚊子找到人类宿主。基本上，这种活动的受体在cpA神经元中表达。在埃及伊蚊和冈比亚按蚊中，这种对二氧化碳敏感的嗅觉神经元能检测出人类皮肤中存在的大量化学物质。因此，操纵容纳这些神经元的味觉受体可能成为行为干预的重要靶点。本研究旨在对味觉受体的保守活性位点残基进行小分子虚拟筛选，并对最佳蛋白质 - 配体复合物进行分子动力学模拟研究，以确定一种合适的先导分子来干扰蚊子寻找宿主的行为。
对埃及伊蚊和冈比亚按蚊的味觉受体（GR）进行保守残基分析。对埃及伊蚊GR蛋白的结构进行建模和验证，然后进行分子对接，以针对GR的预测活性残基筛选2903个小分子。此外，还进行了模拟研究以证明蛋白质 - 配体的稳定性。
发现GR的谷氨酰胺154残基在埃及伊蚊和冈比亚按蚊中高度保守。对接结果表明，十二烷酸1,2,3 - 丙三醇酯（dynasan 112）与该残基相互作用，因为它显示出比先前报道用作驱蚊剂的乙酸乙酯更好的LibDock评分。模拟研究表明，GR蛋白与dynasan 112对接形式的结构不稳定，表明其参与了结构变化。基于相互作用能和稳定性，已提议将该化合物用于制作驱蚊剂。
以丙酮酸乙酯作为标准抑制剂，基于其稳定性、对接评分、相互作用和均方根偏差，提出了一种新型有效的作为GR抑制剂的气味剂。蚊媒的宿主偏好和寻找宿主能力在疾病传播中起关键作用，清楚了解这些方面对于预防疾病传播至关重要。
