Pim-1 激酶是一种丝氨酸/苏氨酸激酶，通常在各种癌症中过度表达，导致疾病进展和预后不良。在这项研究中，我们结合分子对接和引导分子动力学 (SMD) 模拟，探索了类黄酮作为 Pim-1 激酶抑制剂的潜力。我们的对接研究揭示了类黄酮分子的两个主要结合方向。 SMD 模拟表明，较高拉力的结合模式与较强的抑制活性相关，拉力与 IC50 值之间存在很强的正相关性 (R 2 ≈ 0.92)。槲皮素脱颖而出，成为最有效的抑制剂，其拉力约为 820 pN，IC_(5) 0 小于 6 µM。进一步的动力学模拟表明，槲皮素的C3、C-5和C-7位羟基分别与关键残基GLU-121、Leu-44和Val-126形成稳定的氢键，从而增强了其结合稳定性和有效性。我们的结果强调了 C-3 位羟基的关键作用，它在有效地将这些分子锚定在 Pim-1 激酶活性位点方面发挥着关键作用。 Pim-1 激酶构象变化的主成分分析 (PCA) 表明，槲皮素、高良姜素和山奈酚等有效抑制剂显着限制了酶的灵活性，表明具有潜在的抑制作用。这些发现深入了解类黄酮和 Pim-1 激酶之间的结构相互作用，为未来的实验研究奠定了基础。然而，还需要进一步的研究，包括体外和体内验证，以评估类黄酮在癌症治疗中的药理学相关性和特异性。版权所有 © 2024 Alhadrami、Sayed、Hassan、Alhadrami 和 Rateb。

Pim-1 kinase, a serine/threonine kinase, is often overexpressed in various cancers, contributing to disease progression and poor prognosis. In this study, we explored the potential of flavonoids as inhibitors of Pim-1 kinase using a combination of molecular docking and steered molecular dynamics (SMD) simulations. Our docking studies revealed two main binding orientations for the flavonoid molecules. The SMD simulations showed that the binding mode with higher pulling forces was linked to stronger inhibitory activity, with a strong positive correlation (R 2 ≈ 0.92) between pulling forces and IC50 values. Quercetin stood out as the most potent inhibitor, showing a pulling force of about 820 pN and an IC_(5) 0 of less than 6 µM. Further dynamic simulations indicated that quercetin's hydroxyl groups at the C3, C-5 and C-7 positions formed stable hydrogen bonds with key residues GLU-121, Leu-44 and Val-126, respectively enhancing its binding stability and effectiveness. Our results emphasized the critical role of the hydroxyl group at the C-3 position, which plays a pivotal function in effectively anchoring these molecules in the active site of Pim-1 kinase. Principal component analysis (PCA) of Pim-1 kinase's conformational changes revealed that potent inhibitors like quercetin, galangin, and kaempferol significantly restricted the enzyme's flexibility, suggesting potential inhibitory effect. These findings provide insights into the structural interactions between flavonoids and Pim-1 kinase, offering a foundation for future experimental investigations. However, further studies, including in vitro and in vivo validation, are necessary to assess the pharmacological relevance and specificity of flavonoids in cancer therapy.Copyright © 2024 Alhadrami, Sayed, Hassan, Alhadrami and Rateb.