1. Computational investigations of flavonoids as ALDH isoform inhibitors for treatment of cancer.
- Author
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Mohamed MA, Elsaman T, Mohamed MS, and Eltayib EM
- Subjects
- Humans, Neoplasms drug therapy, Quantitative Structure-Activity Relationship, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Isoenzymes antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Molecular Dynamics Simulation, Flavonoids chemistry, Flavonoids pharmacology, Aldehyde Dehydrogenase antagonists & inhibitors, Aldehyde Dehydrogenase chemistry, Aldehyde Dehydrogenase metabolism, Molecular Docking Simulation
- Abstract
Human aldehyde dehydrogenases (ALDHs) are a group of 19 isoforms often overexpressed in cancer stem cells (CSCs). These enzymes play critical roles in CSC protection, maintenance, cancer progression, therapeutic resistance, and poor prognosis. Thus, targeting ALDH isoforms offers potential for innovative cancer treatments. Flavonoids, known for their ability to affect multiple cancer-related pathways, have shown anticancer activity by downregulating specific ALDH isoforms. This study aimed to evaluate 830 flavonoids from the PubChem database against five ALDH isoforms (ALDH1A1, ALDH1A2, ALDH1A3, ALDH2, ALDH3A1) using computational methods to identify potent inhibitors. Extra precision (XP) Glide docking and MM-GBSA free binding energy calculations identified several flavonoids with high binding affinities. MD simulation highlighted flavonoids 1, 2, 18, 27, and 42 as potential specific inhibitors for each isoform, respectively. Flavonoid 10 showed high binding affinities for ALDH1A2, ALDH1A3, and ALDH3A1, emerging as a potential multi-ALDH inhibitor. ADMET property evaluation indicated that the promising hits have acceptable drug-like profiles, but further optimization is needed to enhance their therapeutic efficacy and reduce toxicity, making them more effective ALDH inhibitors for future cancer treatment.
- Published
- 2024
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