Computational investigations of flavonoids as ALDH isoform inhibitors for treatment of cancer

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.人类醛脱氢酶（aldehyde dehydrogenases, ALDHs）是一类包含19种同工酶的蛋白家族，常在癌症干细胞（cancer stem cells, CSCs）中呈高表达状态。这类酶在癌症干细胞的保护、维持、肿瘤进展、治疗耐药及不良预后中发挥关键作用。因此，靶向ALDH同工酶可为创新型癌症治疗提供潜在思路。黄酮类化合物因能够调控多条癌症相关通路而被广泛研究，其可通过下调特定ALDH同工酶发挥抗癌活性。本研究借助计算方法，对来自PubChem数据库的830种黄酮类化合物开展针对5种ALDH同工酶（ALDH1A1、ALDH1A2、ALDH1A3、ALDH2、ALDH3A1）的活性筛选，以识别强效抑制剂。通过超高精度（Extra precision, XP）Glide分子对接及MM-GBSA自由结合能计算，本研究筛选出数种具有高结合亲和力的黄酮类化合物。分子动力学模拟（molecular dynamics simulation, MD）结果显示，黄酮类化合物1、2、18、27及42分别为对应ALDH同工酶的潜在特异性抑制剂。黄酮类化合物10则对ALDH1A2、ALDH1A3及ALDH3A1均表现出高结合亲和力，有望成为潜在的多靶点ALDH抑制剂。ADMET（吸收、分布、代谢、排泄、毒性）性质评估结果表明，上述具有开发潜力的候选化合物具备合格的类药特性，但仍需进一步优化以提升其治疗效能并降低毒性，从而使其成为更高效的ALDH抑制剂，用于未来的癌症治疗研究。