Bhattacharjee Apurba K
Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Curr Comput Aided Drug Des. 2013 Sep;9(3):308-16. doi: 10.2174/15734099113099990021.
PMD (p-menthane-3-8-diol) is an insect repellent that can be synthesized chemically or derived from a steam distillate residue of the leaves of lemon eucalyptus, Corymbia citriodora. It is one of the few natural product endorsed by the Center for Disease Control (USA) for topical application to protect against mosquitoes though it is not as effective as the common repellent DEET (N,N -diethyl-1,3-toluamide). However, DEET has several undesirable side effects and toxicity too. Thus, although PMDs are comparatively safer than DEET, no quantitative structure activity relationship (QSAR) and pharmacophore modeling studies have been reported in literature to improve efficacy and aid further development of more effective PMD analogues. In this study, we report results of quantum chemical analysis of stereoelectronic properties and pharmacophore modeling of PMD and eight of its synthetic derivatives to aid discovery and design of more effective PMD analogues. Stereo-electronic analysis indicates that lower aqueous stabilization (favorable lipophilicity) and larger separation of electrostatic potential energy together with a large localized negative electrostatic potential region by the oxygen atom play important roles for repellent activity. Consistent to these properties, the generated pharmacophore model of the PMDs showed two aliphatic hydrophobic and a hydrogen-bond donor features for potent activity. These results aided us to design more effective PMD repellents which are currently under further investigations.
PMD（对薄荷烷-3,8-二醇）是一种驱虫剂，可通过化学合成或从柠檬桉（Corymbia citriodora）树叶的蒸汽蒸馏残渣中提取得到。它是美国疾病控制中心认可的少数几种可局部使用以防止蚊虫叮咬的天然产物之一，不过其效果不如常见的驱虫剂避蚊胺（N,N-二乙基-1,3-甲苯酰胺）。然而，避蚊胺也有一些不良副作用和毒性。因此，尽管PMD相对避蚊胺更安全，但尚未有文献报道关于定量构效关系（QSAR）和药效团建模研究，以提高其功效并助力开发更有效的PMD类似物。在本研究中，我们报告了对PMD及其八种合成衍生物的立体电子性质进行量子化学分析以及药效团建模的结果，以帮助发现和设计更有效的PMD类似物。立体电子分析表明，较低的水稳定性（有利的亲脂性）、静电势能的较大分离以及氧原子形成的大的局部负静电势区域对驱虫活性起着重要作用。与这些性质一致，生成的PMD药效团模型显示出两个脂肪族疏水特征和一个氢键供体特征以实现强效活性。这些结果有助于我们设计更有效的PMD驱虫剂，目前这些驱虫剂正在进一步研究中。
