Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
Toxicol Lett. 2018 Sep 1;293:184-189. doi: 10.1016/j.toxlet.2017.10.024. Epub 2017 Oct 31.
Irreversible inhibition of the acetylcholine esterase upon intoxication with organophosphorus compounds leads to an accumulation of acetylcholine in the synaptic cleft and a subsequent desensitization of nicotinic acetylcholine receptors which may ultimately result in respiratory failure. The bispyridinium compound MB327 has been found to restore functional activity of nAChR thus representing a promising starting point for the development of new drugs for the treatment of organophosphate poisoning. In order to optimize the resensitizing effect of MB327 on nAChR, it would be very helpful to know the MB327 specific binding site to apply structure based molecular modeling. The binding site for MB327 at the nAChR is not known and so far goal of speculations, but it has been shown that MB327 does not bind to the orthosteric acetylcholine binding site. We have used docking calculations to screen the surface of nAChR for possible binding sites of MB327. The results indicate that at least two potential binding sites for MB327 at nAChR are present inside the channel pore. In these binding sites, MB327 intercalates between the γ-α and β-δ subunits of nAChR, respectively. Both putative MB327 binding sites show an unsymmetrical distribution of surrounding hydrophilic and lipophilic amino acids. This suggests that substitution of MB327-related bispyridinium compounds on one of the two pyridinium rings with polar substituents should have a favorable effect on the pharmacological function.
有机磷化合物中毒会不可逆地抑制乙酰胆碱酯酶，导致乙酰胆碱在突触间隙积聚，随后烟碱型乙酰胆碱受体脱敏，最终可能导致呼吸衰竭。双吡啶化合物 MB327 已被发现可恢复 nAChR 的功能活性，因此代表了开发治疗有机磷中毒的新药的有前途的起点。为了优化 MB327 对 nAChR 的再敏化作用，如果知道 MB327 与 nAChR 的特异性结合位点，应用基于结构的分子建模将非常有帮助。MB327 在 nAChR 上的结合位点尚不清楚，迄今为止一直是推测的目标，但已经表明 MB327 不会与正位乙酰胆碱结合位点结合。我们使用对接计算筛选 nAChR 表面上 MB327 的可能结合位点。结果表明，nAChR 内的通道孔中至少存在两个 MB327 的潜在结合位点。在这些结合位点中，MB327 分别插入 nAChR 的 γ-α 和 β-δ 亚基之间。两个假定的 MB327 结合位点都显示出周围亲水和疏水性氨基酸的不对称分布。这表明，用极性取代基取代两个吡啶环之一上的 MB327 相关双吡啶化合物应该对药理学功能有有利影响。
