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酶动力学决定了针对传播疾病蚊子的抑制剂的效力和选择性。

Enzyme Dynamics Determine the Potency and Selectivity of Inhibitors Targeting Disease-Transmitting Mosquitoes.

机构信息

Department of Chemistry, Umeå University, Umeå SE-90187, Sweden.

CBRN Defense and Security, Swedish Defense Research Agency, Umeå SE-90621, Sweden.

出版信息

ACS Infect Dis. 2024 Oct 11;10(10):3664-3680. doi: 10.1021/acsinfecdis.4c00531. Epub 2024 Sep 18.

Abstract

Vector control of mosquitoes with insecticides is an important tool for preventing the spread of mosquito-borne diseases including malaria, dengue, chikungunya, and Zika. Development of active ingredients for insecticides are urgently needed because existing agents exhibit off-target toxicity and are subject to increasing resistance. We therefore seek to develop noncovalent inhibitors of the validated insecticidal target acetylcholinesterase 1 (AChE1) from mosquitoes. Here we use molecular dynamics simulations to identify structural properties essential for the potency of reversible inhibitors targeting AChE1 from (AChE1), the malaria-transmitting mosquito, and for selectivity relative to the vertebrate AChE (AChE). We show that the collective motions of apo AChE1 and AChE differ, with AChE1 exhibiting less dynamic movement. Opening and closing of the gorge, which regulates access to the catalytic triad, is enabled by different mechanisms in the two species, which could be linked to their differing amino acid sequences. Inhibitor binding reduced the overall magnitude of dynamics of AChE. In particular, more potent inhibitors reduced the flexibility of the Ω loop at the entrance of the gorge. The selectivity of inhibitors for AChE1 over AChE derives from the positioning of the α-helix lining the binding gorge. Our findings emphasize the need to consider dynamics when developing inhibitors targeting this enzyme and highlight factors needed to create potent and selective AChE1 inhibitors that could serve as active ingredients to combat disease-transmitting mosquitoes.

摘要

利用杀虫剂进行蚊虫矢量控制是预防包括疟疾、登革热、基孔肯雅热和寨卡病毒在内的蚊媒疾病传播的重要手段。由于现有药剂具有非靶向毒性,并面临着日益增加的抗药性,因此迫切需要开发杀虫剂的活性成分。因此,我们试图开发针对蚊虫中已验证的杀虫靶标乙酰胆碱酯酶 1(AChE1)的非共价抑制剂。在这里,我们使用分子动力学模拟来识别针对来自 (AChE1)的 AChE1 的可逆抑制剂的效力至关重要的结构特性,以及相对于脊椎动物 AChE(AChE)的选择性。我们表明,apo AChE1 和 AChE 的集体运动不同,AChE1 的运动性较小。峡谷的打开和关闭调节了对催化三联体的进入,两种物种的机制不同,这可能与其不同的氨基酸序列有关。抑制剂结合降低了 AChE 的整体动力学幅度。特别是,更有效的抑制剂降低了峡谷入口处 Ω 环的柔韧性。抑制剂对 AChE1 的选择性优于 AChE 源于排列在结合峡谷中的α-螺旋。我们的研究结果强调了在开发针对该酶的抑制剂时需要考虑动力学的必要性,并突出了创造强效和选择性 AChE1 抑制剂所需的因素,这些抑制剂可以作为对抗传播疾病的蚊子的有效成分。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3644/11474975/0c58ad5d737d/id4c00531_0001.jpg

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