Yilin Gao

Bromodomain-Containing Protein 4 (BRD4) can play an important role in gene transcriptional regulation of tumor development and survival by participating in histone modification epigenetic mechanism. Although it has been reported that novel allosteric inhibitors such as ZL0590 have a high affinity with target protein BRD4 and good efficacy, their inhibitory mechanism has not been studied further. The aim of this study was to reveal the inhibition mechanism of allosteric inhibitor ZL0590 on Free-BRD4 and BRD4 binding MS436 (orthosteric inhibitor) by molecular dynamics simulation combined with a Markov model. Our results showed that BRD4-ZL0590 led to α-helices formation of 100–105 compared with Free-BRD4; the combination of MS436 caused residues 30–40 and 95–105 to form α-helices, while the combination of allosteric inhibitors untangled the α-helices formed by the MS436. The results of Markov flux analysis showed that the binding process of inhibitors mainly involved changes in the degree of α-helices at ZA loop. The binding of ZL0590 reduced the distance between ZA loop and BC loop, blocked the conformation at the active site, and inhibited the binding of MS436. After the allosteric inhibitor binding, the MS436 that could normally penetrate into the interior of the pocket was floating on the edge of the active pocket and did not continue to penetrate into the active pocket as expected. In summary, we provide a theoretical basis for the inhibition mechanism of ZL0590 against BRD4, which can be used as a reference for improving the development of drug targets for cancer therapy.

The accumulation of cross-β-sheet amyloid fibrils is a hallmark of the neurodegenerative process of Alzheimer’s disease (AD). Although it has been reported that green tea substances such as epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC) and epigallocatechin-3-gallate (EGCG) could alleviate the symptoms of AD and other neurodegenerative diseases, the pharmacological mechanism remains largely unexplored. This study aimed to reveal the underlying mechanism of EC, ECG, EGC and EGCG in AD using a computer-aided screening strategy. Our results showed that the four tea polyphenols interfered with the signaling pathways of AD via calcium signaling channels, neurodegeneration-multiple disease signal pathways and others. We also identified the key residues of the interaction between VEGFA and the four active components, which included Glu64 and Phe36. Overall, we have provided valuable insights into the molecular mechanism of tea polyphenols, which could be used as a reference to improve therapeutic strategies against AD.