类黄酮的分子见解和抑制性动力学靶向PIM-1激酶进行癌症治疗
Molecular insights and inhibitory dynamics of flavonoids in targeting Pim-1 kinase for cancer therapy
影响因子:4.80000
分区:医学3区 / 药学3区
发表日期:2024
作者:
Hani A Alhadrami, Ahmed M Sayed, Hossam M Hassan, Albaraa H Alhadrami, Mostafa E Rateb
摘要
PIM-1激酶是一种丝氨酸/苏氨酸激酶，通常在各种癌症中过表达，导致疾病进展和预后不良。在这项研究中，我们使用分子对接和转导分子动力学（SMD）模拟的组合探索了类黄酮作为PIM-1激酶的抑制剂的潜力。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，具有较高拉动力的结合模式与较强的抑制活性有关，拉力和IC50值之间具有强的正相关（r2≈0.92）。槲皮素是最有效的抑制剂，表现出约820 pn的拉力和小于6 µm的IC_（5）0。进一步的动态模拟表明，在C3，C-5和C-7位置处的槲皮素的羟基形成了稳定的氢键，其具有关键残基GLU-121，LEU-44和Val-126，从而增强了其结合稳定性和有效性。我们的结果强调了羟基在C-3位置的关键作用，该位置在有效地锚定这些分子的PIM-1激酶的活性位点时起着关键功能。 PIM-1激酶构象变化的主要成分分析（PCA）表明，槲皮素，加兰吉宁和凯恩植物等有效的抑制剂显着限制了该酶的柔韧性，表明潜在的抑制作用。这些发现为类黄酮和PIM-1激酶之间的结构相互作用提供了见解，为将来的实验研究提供了基础。然而，进一步的研究，包括体外和体内验证，对于评估癌症治疗中类黄酮的药理相关性和特异性是必要的。
Abstract
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.