Exploring the Potentiality of Natural Products from Essential Oils as Inhibitors of Odorant-Binding Proteins: A Structure- and Ligand-Based Virtual Screening Approach To Find Novel Mosquito Repellents

Odorant-binding proteins (OBPs) are the main olfactory
proteins
of mosquitoes, and their structures have been widely explored to develop
new repellents. In the present study, we combined ligand- and structure-based
virtual screening approaches using as a starting point 1633 compounds
from 71 botanical families obtained from the Essential Oil Database
(EssOilDB). Using as reference the crystallographic structure of N,N-diethyl-meta-toluamide
interacting with the OBP1 homodimer of Anopheles gambiae (AgamOBP1), we performed a structural and pharmacophoric
similarity search to select potential natural products from the library. Thymol acetate, 4-(4-methyl phenyl)-pentanal, thymyl isovalerate,
and p-cymen-8-yl demonstrated a favorable chemical
correlation with DEET and also had high-affinity interactions with
the OBP binding pocket that molecular dynamics simulations showed
to be stable. To the best of our knowledge, this is the first study
to evaluate on a large scale the potentiality of NPs from essential
oils as inhibitors of the mosquito OBP1 using in silico approaches.
Our results could facilitate the design of novel repellents with improved
selectivity and affinity to the protein binding pocket and can shed
light on the mechanism of action of these compounds against insect
olfactory recognition.

嗅觉结合蛋白（OBPs）是蚊子主要的嗅觉蛋白，其结构已被广泛研究以开发新型驱蚊剂。在本研究中，我们结合了基于配体和结构的虚拟筛选方法，以71个科植物的1633个化合物作为起始点，这些化合物来源于精油数据库（EssOilDB）。以N,N-二乙基间甲苯酰胺与冈比亚按蚊OBP1同源二聚体（AgamOBP1）的晶体结构为参考，我们进行了结构和药效相似性搜索，以从化合物库中选择潜在的天然产物。乙酸麝香草酚、4-(4-甲基苯基)-戊醛、麝香草基异戊酸和对伞花烃-8-醇表现出与DEET有利的化学相关性，并且与OBP结合口袋具有高亲和力相互作用，分子动力学模拟显示该口袋稳定。据我们所知，这是首次大规模评估精油中的天然产物作为蚊子OBP1抑制剂潜力的研究。我们的结果可能有助于设计新型驱蚊剂，这些驱蚊剂对蛋白结合口袋具有改进的选择性和亲和力，并可能阐明这些化合物对抗昆虫嗅觉识别的作用机制。