Baicalein is a novel TLR4‐targeting therapeutics agent that inhibits TLR4/HIF‐1α/VEGF signaling pathway in colorectal cancer

In our study, molecular docking showed that baicalein directly bound to TLR4 protein (binding energy -6.6 kcal/mol), which was the same as the binding energy between TLR4 and TAK242.1 Three-dimensional ribbon model of the baicalein-TLR4 complex showed that hydrogen bonds were formed between the backbone of TLR4 at PHE-573, ALA-572, VAL-548, GLN-547, VAL-524, PHE-500, THR-499, VAL-475 (Figure 1A), and the system was stable during simulation (Figure 1B). The anti-angiogenic effect of baicalein was also demonstrated by the reduced blood vessel formation in the chick yolk sac membrane (Figure 3J), reduced vessel sprouting in the rat aortic ring model (Figure 3K), and cultured human vascular endothelial cells (Figure 3L). Currently, TLR4 antagonists designed based on the modification of the lipid A4 structure,9 the LPS innermost region, may not have potent inhibitory effect because NMR study shows that the presence of the fatty acyl chain of the lipid A moiety is not necessary for driving TLR4 activation.10 In conclusion, we report the discovery that baicalein directly binds to TLR4 and inhibits TLR4/HIF-1α/VEGF signaling pathway in CRC.