Abstract：
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.
摘要：
AKR1B1和AKR1B10是aldo-keto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，反应性醛的解毒，以及各种内源性和外源性化合物的减少。本研究旨在通过药物再利用的方法，以AKR1B1和AKR1B10为靶点，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，确认其适合进一步调查。此外,进行了密度泛函理论(DFT)研究，以深入了解有助于药物分子反应性的电子性质。在有希望的DFT结果的基础上，使用AutoDock工具进行分子对接分析，以检查士的宁和建议的目标之间的结合相互作用，AKR1B1和AKR1B10。分子对接研究的结果表明，士的宁作为AKR1B1和AKR1B10抑制剂的可能性更高，对接得分分别为-30.84和-29.36kJ/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稳定复合物的形成。这种全面的方法揭示了士的宁作为乳房治疗的潜在有效性，肺，肝脏,和胰腺癌，以及相关的恶性肿瘤。从基于生理的药代动力学建模中获得的新见解，密度泛函理论，分子对接,和分子动力学模拟共同支持士的宁作为抗癌治疗的有前途的分子的前景。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。
