Gade Anushree Chandrashekhar, Murahari Manikanta, Pavadai Parasuraman, Kumar Maushmi Shailesh
Somaiya Institute of Research and Consultancy, Somaiya Vidyavihar University, Mumbai 400077, India.
Department of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522302, India.
Life (Basel). 2023 May 31;13(6):1298. doi: 10.3390/life13061298.
Alzheimer's disease is characterized by amyloid-beta aggregation and neurofibrillary tangles. Acetylcholinesterase (AChE) hydrolyses acetylcholine and induces amyloid-beta aggregation. Acetylcholinesterase inhibitors (AChEI) inhibit this aggregation by binding to AChE, making it a potential target for the treatment of AD. In this study, we have focused on the identification of potent and safe AChEI from the Comprehensive Marine Natural Product Database (CMNPD) using computational tools. For the screening of CMNPD, a structure-based pharmacophore model was generated using a structure of AChE complexed with the co-crystallized ligand galantamine (PDB ID: 4EY6). The 330 molecules that passed through the pharmacophore filter were retrieved, their drug-likeness was determined, and they were then subjected to molecular docking studies. The top ten molecules were selected depending upon their docking score and were submitted for toxicity profiling. Based on these studies, molecule 64 (CMNPD8714) was found to be the safest and was subjected to molecular dynamics simulations and density functional theory calculations. This molecule showed stable hydrogen bonding and stacked interactions with TYR341, mediated through a water bridge. In silico results can be correlated with in vitro studies for checking its activity and safety in the future.
阿尔茨海默病的特征是β-淀粉样蛋白聚集和神经原纤维缠结。乙酰胆碱酯酶（AChE）水解乙酰胆碱并诱导β-淀粉样蛋白聚集。乙酰胆碱酯酶抑制剂（AChEI）通过与AChE结合来抑制这种聚集，使其成为治疗阿尔茨海默病的潜在靶点。在本研究中，我们利用计算工具，专注于从综合海洋天然产物数据库（CMNPD）中鉴定高效且安全的AChEI。为了筛选CMNPD，使用与共结晶配体加兰他敏复合的AChE结构（PDB ID：4EY6）生成了基于结构的药效团模型。检索到330个通过药效团筛选的分子，测定了它们的类药性，然后对其进行分子对接研究。根据对接分数选择了排名前十的分子，并提交进行毒性分析。基于这些研究，发现分子64（CMNPD8714）是最安全的，并对其进行了分子动力学模拟和密度泛函理论计算。该分子通过水桥与TYR341表现出稳定的氢键和堆积相互作用。计算机模拟结果可与未来的体外研究相关联，以检验其活性和安全性。
