Bondžić Aleksandra M, Lazarević-Pašti Tamara D, Leskovac Andreja R, Petrović Sandra Ž, Čolović Mirjana B, Parac-Vogt Tatjana N, Janjić Goran V
Department of Physical Chemistry, "VINČA" Institute of Nuclear Sciences- National Institute of thе Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia.
Department of Physical Chemistry, "VINČA" Institute of Nuclear Sciences- National Institute of thе Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia.
Eur J Pharm Sci. 2020 Aug 1;151:105376. doi: 10.1016/j.ejps.2020.105376. Epub 2020 May 31.
Acetylcholinesterase (AChE) inhibitors are important in the treatment of neurodegenerative diseases. Two inhibitors, 12-tungstosilicic acid (WSiA) and 12-tungstophosphoric acid (WPA), which have polyoxometalate (POM) type structure, have been shown to inhibit AChE activity in nM concentration. Circular dichroism and tryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significant changes in the secondary structure of the enzyme. The molecular docking approach has revealed a new allosteric binding site, termed β-allosteric site (β-AS), which is considered responsible for the inhibition of AChE by POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is considered responsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selected POMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. It was shown that WSiA and WPA induced a mild cytostatic but not genotoxic effects in human lymphocytes, which indicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable of binding to an allosteric site that so far has not been considered responsible for enzyme inhibition could be fundamental for the development of new drug design strategies and the discovery of more efficient AChE modulators.
乙酰胆碱酯酶（AChE）抑制剂在神经退行性疾病的治疗中具有重要作用。两种具有多金属氧酸盐（POM）型结构的抑制剂，即12-钨硅酸（WSiA）和12-钨磷酸（WPA），已被证明在纳摩尔浓度下就能抑制AChE活性。圆二色光谱和色氨酸荧光光谱表明，AChE的抑制作用并未伴随着该酶二级结构的显著变化。分子对接方法揭示了一个新的变构结合位点，称为β-变构位点（β-AS），该位点被认为是POMs抑制AChE的原因。据我们所知，这是第一项报道一个新的变构位点的研究，该位点被认为是由诸如POMs等体积大且带负电荷的分子抑制AChE的原因。使用人外周血细胞作为模型系统，对所选的POMs进一步进行了遗传毒性测试。结果表明，WSiA和WPA在人淋巴细胞中诱导了轻度的细胞生长抑制作用，但没有遗传毒性作用，这表明它们有作为药物使用的潜力。鉴定出能够结合到一个迄今为止尚未被认为与酶抑制作用有关的变构位点的无毒化合物，可能是开发新的药物设计策略和发现更有效的AChE调节剂的基础。
