AKR1B1 and AKR1B10 are important members of aldo–keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule’s reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of − 30.84 and − 29.36 kJ/mol respectively. To validate the stability of the protein–ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings.

AKR1B1 和 AKR1B10 是醛酮还原酶家族的重要成员，通过调节细胞代谢在癌症进展中发挥重要作用。这些酶参与各种代谢过程，包括激素的合成和代谢、活性醛的解毒以及各种内源性和外源性化合物的还原。本研究旨在通过药物再利用方法，通过靶向 AKR1B1 和 AKR1B10 来探索士的宁作为抗癌药物的潜力。为了评估士的宁的药物样特性，采用了基于生理学的药代动力学 (PKPB) 模型和高通量药代动力学 (HTPK) 方法。获得的结果落在药物分子的预期范围内，证实其适合进一步研究。此外，还进行了密度泛函理论 (DFT) 研究，以深入了解影响药物分子反应性的电子特性。基于有希望的 DFT 结果，使用 AutoDock 工具进行分子对接分析，以检查士的宁与拟议靶标 AKR1B1 和 AKR1B10 之间的结合相互作用。分子对接研究结果表明士的宁作为 AKR1B1 和 AKR1B10 抑制剂的可能性较高，对接分数分别为 − 30.84 和 − 29.36 kJ/mol。为了验证蛋白质-配体复合物的稳定性，进行了分子动力学模拟（MDS）研究，揭示了酶和士的宁之间形成了稳定的复合物。这种综合方法揭示了士的宁治疗乳腺癌、肺癌、肝癌和胰腺癌以及相关恶性肿瘤的潜在功效。从基于生理学的药代动力学模型、密度泛函理论、分子对接和分子动力学模拟中获得的新见解共同支持了士的宁作为一种有前景的抗癌治疗分子的前景。需要进一步的研究来验证这些发现并探索士的宁在临床前和临床环境中的治疗潜力。