Abstract

There are a significant number of cases whereby cancer patients belonging to the old age group additionally suffer from cognition decline (a hallmark feature of Alzheimer’s disease). Hence, it is understandable that it would be a boon if certain drug molecules could provide health benefits to a patient suffering from cancer as well as Alzheimer’s disease. The objective of the work was to identify anticancer molecule(s) whose chemical-skeleton could be used as ‘seed’ for future design of dual-acting drugs against Alzheimer’s disease and cancer. The study employed criterion-based search, docking, SWISS-ADME-profiling, ▵ASA-calculations, molecular-overlay and ‘MoMA’-simulation to query possible binding of selected anticancer molecules with human brain acetylcholinesterase (AChE). Molecular interactions of all of the top ranking ligands were analyzed. ‘BOILED-egg’ model was employed to query brain-penetration of the ligands. A detailed molecular-simulation-analysis was performed. Snapshots of different stages of dynamic molecular interactions (selected from 254 pdb files) were captured by MoMA LigPath, a robotics inspired simulation algorithm. The study concluded that chemical skeletons of ‘Niraparib’ and ‘Ponatinib' might be used as ‘seed(s)’ for design of such drugs. If successfully materialized in future, this approach could decrease the total number of daily pills that an old patient needs to take. Furthermore, novel anticancer drugs could be synthesized that do not inhibit AChE (e.g. by removal/modification of moieties that are crucial to binding of anticancer drug to AChE) even if those happen to be ‘Blood Brain Barrier’-permeable. Alternatively, fresh AChE-inhibitors could be designed based on the scaffolds of the aforementioned anticancer drugs.

Communicated by Ramaswamy H. Sarma

摘要

有相当数量的案例表明，属于老年组的癌症患者还会出现认知衰退（阿尔茨海默病的标志性特征）。因此，如果某些药物分子可以为患有癌症和阿尔茨海默病的患者提供健康益处，那将是一个福音，这是可以理解的。这项工作的目的是确定抗癌分子，其化学骨架可以用作未来设计抗阿尔茨海默病和癌症的双效药物的“种子”。该研究采用基于标准的搜索、对接、SWISS-ADME 分析、▵ASA 计算、分子叠加和“MoMA”模拟来查询选定的抗癌分子与人脑乙酰胆碱酯酶 (AChE) 的可能结合。分析了所有排名靠前的配体的分子相互作用。“煮鸡蛋”模型用于查询配体的脑渗透。进行了详细的分子模拟分析。MoMA LigPath 捕获了动态分子相互作用的不同阶段的快照（选自 254 个 pdb 文件），这是一种受机器人启发的模拟算法。该研究得出结论，“Niraparib”和“Ponatinib”的化学骨架可用作设计此类药物的“种子”。如果将来成功实现，这种方法可以减少老年患者每天需要服用的药片总数。此外，可以合成不抑制AChE的新型抗癌药物（例如，通过去除/修饰对于抗癌药物与AChE的结合至关重要的部分），即使那些恰好是“血脑屏障”-可渗透的。或者，

由 Ramaswamy H. Sarma 传达