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Updated: Dec 4, 2025
A Flow Cytometry-Based Cell Surface Protein Binding Assay for Assessing Selectivity and Specificity of an Anticancer Aptamer
Published on: September 13, 2022
Molecular interaction of anti-cancer ligands with human brain acetylcholinesterase
Shazi Shakil1,2
1King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
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.
Insights
Researchers identified potential dual-action drug candidates for cancer and Alzheimer's disease. The chemical structures of Niraparib and Ponatinib show promise as starting points for developing new therapies.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Oncology
Background:
- Elderly cancer patients often experience cognitive decline, similar to Alzheimer's disease.
- Developing single drugs for both conditions could significantly improve patient quality of life and reduce pill burden.
Purpose of the Study:
- To identify existing anticancer molecules that can be repurposed or modified for dual-action therapy against cancer and Alzheimer's disease.
- To explore the potential of anticancer drug scaffolds as a basis for novel Alzheimer's disease treatments.
Main Methods:
- Utilized criterion-based search, molecular docking, and SWISS-ADME profiling.
- Assessed ligand binding to human brain acetylcholinesterase (AChE) and blood-brain barrier penetration using BOILED-egg model.
- Employed MoMA LigPath for molecular dynamics simulations to analyze interactions.
Main Results:
- Identified Niraparib and Ponatinib as promising anticancer molecules with chemical skeletons suitable for dual-drug design.
- Analyzed molecular interactions and confirmed brain-penetration potential of selected ligands.
- Simulations provided insights into dynamic molecular interactions.
Conclusions:
- The chemical scaffolds of Niraparib and Ponatinib can serve as 'seeds' for designing novel drugs targeting both cancer and Alzheimer's disease.
- This approach may lead to the development of new anticancer drugs that are blood-brain barrier permeable without inhibiting AChE, or new AChE inhibitors based on these scaffolds.
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