PDF(Pubmed)
Abstract：
Neuromuscular blocking agents (NMBAs) are routinely used during anesthesia to relax skeletal muscle. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels; NMBAs can induce muscle paralysis by preventing the neurotransmitter acetylcholine (ACh) from binding to nAChRs situated on the postsynaptic membranes. Despite widespread efforts, it is still a great challenge to find new NMBAs since the introduction of cisatracurium in 1995. In this work, an effective ensemble-based virtual screening method, including molecular property filters, 3D pharmacophore model, and molecular docking, was applied to discover potential NMBAs from the ZINC15 database. The results showed that screened hit compounds had better docking scores than the reference compound d-tubocurarine. In order to further investigate the binding modes between the hit compounds and nAChRs at simulated physiological conditions, the molecular dynamics simulation was performed. Deep analysis of the simulation results revealed that ZINC257459695 can stably bind to nAChRs\' active sites and interact with the key residue Asp165. The binding free energies were also calculated for the obtained hits using the MM/GBSA method. In silico ADMET calculations were performed to assess the pharmacokinetic properties of hit compounds in the human body. Overall, the identified ZINC257459695 may be a promising lead compound for developing new NMBAs as an adjunct to general anesthesia, necessitating further investigations.
摘要：
在麻醉期间常规使用神经肌肉阻断剂(NMBAs)来放松骨骼肌。烟碱乙酰胆碱受体（nAChR）是配体门控离子通道；NMBA可以通过阻止神经递质乙酰胆碱（ACh）与突触后膜上的nAChR结合来诱导肌肉麻痹。尽管进行了广泛的努力，自1995年引入顺式阿曲库铵以来，寻找新的NMBA仍然是一个巨大的挑战。在这项工作中,一种有效的基于集成的虚拟筛选方法，包括分子特性过滤器，3D药效团模型，和分子对接，用于从ZINC15数据库中发现潜在的NMBAs。结果表明，筛选的命中化合物比参考化合物d-tubocurarine具有更好的对接得分。为了进一步研究模拟生理条件下命中化合物与nAChRs的结合模式,分子动力学模拟。对模拟结果的深入分析表明，ZINC257459695可以稳定地结合nAChRs的活性位点，并与关键残基Asp165相互作用。还使用MM/GBSA方法计算获得的命中的结合自由能。进行计算机模拟ADMET计算以评估命中化合物在人体内的药代动力学性质。总的来说,已鉴定的ZINC257459695可能是开发新的NMBA作为全身麻醉的辅助药物的有前途的先导化合物，需要进一步调查。
