黄酮类化合物靶向Pim-1激酶的分子机制与抑制作用研究

Molecular insights and inhibitory dynamics of flavonoids in targeting Pim-1 kinase for cancer therapy

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Frontiers in Pharmacology

影响因子:4.8

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

DOI: 10.3389/fphar.2024.1440958

摘要

Pim-1激酶是一种丝氨酸/苏氨酸激酶，在多种癌症中呈现过度表达，促进疾病进展并预后不良。本研究结合分子对接和定向分子动力学（SMD）模拟，探讨了黄酮类化合物作为Pim-1激酶抑制剂的潜力。对接结果显示，黄酮分子存在两种主要结合构象。SMD模拟表明，拉力较大的结合模式对应更强的抑制活性，两者之间呈显著正相关（R^2≈0.92），拉力与IC50值呈反比关系。槲皮素表现出最强的抑制作用，拉力约为820 pN，IC50小于6 μM。动态模拟进一步显示，槲皮素的C3、C-5和C-7位置的羟基能与关键残基GLU-121、Leu-44和Val-126形成稳定的氢键，增强结合稳定性和抑制效果。研究强调C-3羟基在药物与Pim-1激酶活性位点结合中的关键作用。Pim-1激酶构象变化的主成分分析（PCA）显示，像槲皮素、金缕梅素和山奈酚等强效抑制剂显著限制酶的柔韧性，提示其潜在的抑制效果。这些发现为黄酮类与Pim-1激酶的结构相互作用提供了理论基础，为未来的体外和体内验证奠定了基础，但需要进一步研究以评估其在癌症治疗中的药理学相关性和特异性。

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.