College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China.
College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China.
Life Sci. 2021 Apr 1;270:119141. doi: 10.1016/j.lfs.2021.119141. Epub 2021 Jan 30.
Although the proteins in bromodomain and extra-terminal domain (BET) family are promising therapy drug targets for numerous human diseases, the binding effectiveness is interfered by the competition from non-BET protein BRD9. In this study, molecular docking, molecular dynamics simulations, binding free energy calculations and per-residue energy decomposition methods were employed to clarify the selective inhibition mechanism of nitroxoline. The results showed that the different cavity volume of effective embedding inhibitor and the changes in conserved residues were associated with the significant higher selectivity of inhibitor nitroxoline for BET family than non-BET protein (BRD9). In addition, the non-polar interactions occurred in Phe83, Val87 at ZA loop, and the polar interaction appeared in Met132, Asn135 at BC loop. Therefore, when designing a new inhibitor, it could better improve the inhibitor activity by introducing the heteroatom conjugated pyridine-like moiety and the strong electron-withdrawing nitro-like moiety. Overall, this study not only clarified the molecular mechanism of the selective inhibition of nitroxoline, but also provided insight into designing more effective BET inhibitors in next step.
尽管溴结构域和末端结构域（BET）家族的蛋白质是许多人类疾病有前途的治疗药物靶点，但它们的结合效果会受到非 BET 蛋白 BRD9 的竞争的干扰。在这项研究中，采用分子对接、分子动力学模拟、结合自由能计算和残基能量分解方法，阐明了硝呋罗啉的选择性抑制机制。结果表明，有效嵌入抑制剂的不同腔体积和保守残基的变化与抑制剂硝呋罗啉对 BET 家族的选择性明显高于非 BET 蛋白（BRD9）有关。此外，ZA 环中的苯丙氨酸 83 位和缬氨酸 87 位发生非极性相互作用，BC 环中的蛋氨酸 132 位和天冬酰胺 135 位发生极性相互作用。因此，在设计新的抑制剂时，可以通过引入杂原子共轭吡啶类似物和强吸电子硝基类似物来更好地提高抑制剂的活性。总的来说，这项研究不仅阐明了硝呋罗啉选择性抑制的分子机制，还为下一步设计更有效的 BET 抑制剂提供了思路。
