Department of Drug Sciences, University of Catania, V.le A. Doria, 95125, Catania, Italy.
Villa Beretta Rehabilitation Center, Valduce Hospital, 23845, Costa Masnaga, Lecco, Italy.
ChemMedChem. 2020 Jan 17;15(2):256-262. doi: 10.1002/cmdc.201900594. Epub 2019 Dec 9.
Botulinum neurotoxin (BoNT) is widely used for the treatment of spasticity, focal dystonia, chronic migraine, facial hemispasm, and facial aesthetic treatments. Generally, treatment with botulinum toxin is a safe procedure when conducted by clinicians with expertise, and local side effects are rare and transient. However, occasionally adverse effects can occur due to the spread of the drug to nontargeted muscles and organs, producing dry mouth, fatigue, and flu-like symptoms, up to signs of systemic botulism, which appears to be more frequent in children treated for spasticity than in adults. In silico 3D-QSAR and molecular docking studies were performed to build a structure-based model on selected potent known botulinum neurotoxin type A inhibitors; this was used to screen the US Food and Drug Administration (FDA) database. Thirty molecules were identified as possible light-chain BoNT/A inhibitors. In this study, we applied a well-established ligand- and structure-based methodology for the identification of hit compounds among a database of FDA-approved drugs. The identification of budesonide, protirelin, and ciclesonide followed by other compounds can be considered a starting point for investigations of selected compounds that could bypass much of the time and costs involved in the drug approval process.
肉毒杆菌神经毒素（BoNT）广泛用于治疗痉挛、局灶性肌张力障碍、慢性偏头痛、面部痉挛和面部美容治疗。通常，由具有专业知识的临床医生进行肉毒毒素治疗是一种安全的程序，局部副作用罕见且短暂。然而，偶尔会由于药物扩散到非目标肌肉和器官而产生不良反应，产生口干、疲劳和流感样症状，甚至出现全身肉毒中毒的迹象，在接受痉挛治疗的儿童中似乎比在成人中更为频繁。进行了基于 3D-QSAR 和分子对接的计算机模拟研究，以构建针对选定的强效已知肉毒神经毒素 A 抑制剂的基于结构的模型；这用于筛选美国食品和药物管理局（FDA）数据库。确定了 30 种分子作为潜在的轻链 BoNT/A 抑制剂。在这项研究中，我们应用了一种成熟的基于配体和结构的方法，在 FDA 批准药物的数据库中鉴定出命中化合物。布地奈德、普罗替林和噻托溴铵的鉴定以及其他化合物的鉴定可以被认为是对选定化合物进行研究的起点，这些化合物可以绕过药物批准过程中涉及的大量时间和成本。
